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600800.9641Photopolymerized keratin-PGLa hydrogels for antibiotic resistance reversal and enhancement of infectious wound healing. Infectious wounds have become serious challenges for both treatment and management in clinical practice, so development of new antibiotics has been considered an increasingly difficult task. Here, we report the design and synthesis of keratin 31 (K31)-peptide glycine-leucine-amide (PGLa) photopolymerized hydrogels to rescue the antibiotic activity of antibiotics for infectious wound healing promotion. K31-PGLa displayed an outstanding synergistic effect with commercial antibiotics against drug-resistant bacteria by down-regulating the synthesis genes of efflux pump. Furthermore, the photopolymerized K31-PGLa/PEGDA hydrogels effectively suppressed drug-resistant bacteria growth and enhanced skin wound closure in murine. This study provided a promising alternative strategy for infectious wound treatment.202337810750
973310.9626The 2018 Garrod Lecture: Preparing for the Black Swans of resistance. The need for governments to encourage antibiotic development is widely agreed, with 'market entry rewards' being suggested. Unless these are to be spread widely-which is unlikely given the $1 billion sums proposed-we should be wary, for this approach is likely to evolve into one of picking, or commissioning, a few 'winners' based on extrapolation of current resistance trends. The hazard to this is that whilst the evolution of resistance has predictable components, notably mutation, it also has completely unpredictable ones, contingent upon 'Black Swan' events. These include the escape of 'new' resistance genes from environmental bacteria and the recruitment of these genes by promiscuous mobile elements and epidemic strains. Such events can change the resistance landscape rapidly and unexpectedly, as with the rise of Escherichia coli ST131 with CTX-M ESBLs and the emergence of 'impossible' VRE. Given such unpredictability, we simply cannot say with any certainty, for example, which of the four current approaches to combating MBLs offers the best prospect of sustainable prizeworthy success. Only time will tell, though it is encouraging that multiple potential approaches to overcoming these problematic enzymes are being pursued. Rather than seeking to pick winners, governments should aim to reduce development barriers, as with recent relaxation of trial regulations. In particular, once β-lactamase inhibitors have been successfully trialled with one partner drug, there is scope to facilitate licensing them for partnering with other established β-lactams, thereby insuring against new emerging resistance.201830351434
902620.9623Citral and its derivatives inhibit quorum sensing and biofilm formation in Chromobacterium violaceum. With an upsurge in multidrug resistant bacteria backed by biofilm defence armours, there is a desperate need of new antibiotics with a non-traditional mechanism of action. Targeting bacteria by misguiding them or halting their communication is a new approach that could offer a new way to combat the multidrug resistance problem. Quorum sensing is considered to be the achilles heel of bacteria that has a lot to offer. Since, both quorum sensing and biofilm formation have been related to drug resistance and pathogenicity, in this study we synthesised new derivatives of citral with antiquorum sensing and biofilm disrupting properties. We previously reported antimicrobial and antiquorum sensing activity of citral and herein we report the synthesis and evaluation of citral and its derivatives (CD1-CD3) for antibacterial, antibiofilm and antiquorum sensing potential against Chromobacterium violaceum using standard methods. Preliminary results revealed that CD1 is the most active of all the derivatives. Qualitative and quantitative evaluation of antiquorum sensing activity at sub-inhibitory concentrations of these compounds also revealed high activity for CD1 followed by CD2, CD3 and citral. These compounds also inhibit biofilm formation at subinhibitory concentrations without causing any bacterial growth inhibition. These results were replicated by RT-qPCR with down regulation of the quorum sensing genes when C. violaceum was treated with these test compounds. Overall, the results are quite encouraging, revealing that biofilm and quorum sensing are interrelated processes and also indicating the potential of these derivatives to impede bacterial communication and biofilm formation.202133392626
11430.9618A novel enzyme conferring streptothricin resistance alters the toxicity of streptothricin D from broad-spectrum to bacteria-specific. Streptothricins (STs) produced by Streptomyces strains are broad-spectrum antibiotics. All STs consist of a carbamoylated D-gulosamine to which the beta-lysine homopolymer (1 to 7 residues) and the amide form of the unusual amino acid streptolidine (streptolidine lactam) are attached. Although many ST-resistance genes have been identified in bacteria, including clinically isolated pathogens and ST-producing Streptomyces strains, only one resistance mechanism has been identified to date. This mechanism involves the modification of the ST molecule by monoacetylation of the moiety of the beta-lysine(s). In this study, we successfully isolated a novel ST-resistance gene (sttH) from Streptomyces albulus, which is a known ST nonproducer. The in vitro analysis of SttH demonstrated that this enzyme catalyzes the hydrolysis of the amide bond of streptolidine lactam, thereby conferring ST resistance. Interestingly, the selective toxicity of ST-D possessing 3x beta-lysine moiety was altered from broad-spectrum to bacteria-specific by the hydrolysis of streptolidine lactam, although ST-F (1 x beta-lysine) was detoxified by SttH in both prokaryotes and eukaryotes (yeasts). STs have not been clinically developed due to their toxicities; however, in this study, we showed that hydrolyzed ST-D (ST-D-acid) exhibits potent antibacterial activity even when its toxicity against eukaryotic cells is reduced by SttH. This suggests that ST-D-acid is a potential candidate for clinical development or for use as a new lead compound for drug discovery.200616641084
841940.9617The uncultured luminous symbiont of Anomalops katoptron (Beryciformes: Anomalopidae) represents a new bacterial genus. Flashlight fishes (Beryciformes: Anomalopidae) harbor luminous symbiotic bacteria in subocular light organs and use the bacterial light for predator avoidance, feeding, and communication. Despite many attempts anomalopid symbionts have not been brought into laboratory culture, which has restricted progress in understanding their phylogenetic relationships with other luminous bacteria, identification of the genes of their luminescence system, as well as the nature of their symbiotic interactions with their fish hosts. To begin addressing these issues, we used culture-independent analysis of the bacteria symbiotic with the anomalopid fish, Anomalops katoptron, to characterize the phylogeny of the bacteria and to identify the genes of their luminescence system including those involved in the regulation of luminescence. Analysis of the 16S rRNA, atpA, gapA, gyrB, pyrH, recA, rpoA, and topA genes resolved the A. katoptron symbionts as a clade nested within and deeply divergent from other members of Vibrionaceae. The bacterial luminescence (lux) genes were identified as a contiguous set (luxCDABEG), as found for the lux operons of other luminous bacteria. Phylogenetic analysis based on the lux genes confirmed the housekeeping gene phylogenetic placement. Furthermore, genes flanking the lux operon in the A. katoptron symbionts differed from those flanking lux operons of other genera of luminous bacteria. We therefore propose the candidate name Candidatus Photodesmus (Greek: photo = light, desmus = servant) katoptron for the species of bacteria symbiotic with A. katoptron. Results of a preliminary genomic analysis for genes regulating luminescence in other bacteria identified only a Vibrio harveyi-type luxR gene. These results suggest that expression of the luminescence system might be continuous in P. katoptron.201121864694
874250.9615Effect of Bacteria and Bacterial Constituents on Recovery and Resistance of Tulane Virus. Noroviruses encounter numerous and diverse bacterial populations in the host and environment, but the impact of bacteria on norovirus transmission, infection, detection, and inactivation are not well understood. Tulane virus (TV), a human norovirus surrogate, was exposed to viable bacteria, bacterial metabolic products, and bacterial cell constituents and was evaluated for impact on viral recovery, propagation, and inactivation resistance, respectively. TV was incubated with common soil, intestinal, skin, and phyllosphere bacteria, and unbound viruses were recovered by centrifugation and filtration. TV recovery from various bacterial suspensions was not impeded, which suggests a lack of direct, stable binding between viruses and bacteria. The cell-free supernatant (CFS) of Bifidobacterium bifidum 35914, a bacterium that produces glycan-modifying enzymes, was evaluated for effect on the propagation of TV in LLC-MK2 cells. CFS did not limit TV propagation relative to TV absent of CFS. The impact of Escherichia coli O111:B4 lipopolysaccharide (LPS) and Bacillus subtilis peptidoglycan (PEP) on TV thermal and chlorine inactivation resistance was evaluated. PEP increased TV thermal and chlorine inactivation resistance compared with control TV in phosphate-buffered saline (PBS). TV suspended in PBS and LPS was reduced by more than 3.7 log at 60°C, whereas in PEP, TV reduction was approximately 2 log. Chlorine treatment (200 ppm) rendered TV undetectable (>3-log reduction) in PBS and LPS; however, TV was still detected in PEP, reduced by 2.9 log. Virus inactivation studies and food processing practices should account for potential impact of bacteria on viral resistance.202032221571
664960.9615 The development of antibiotics has provided much success against infectious diseases in animals and humans. But the intensive and extensive use of antibiotics over the years has resulted in the emergence of drug-resistant bacterial pathogens. The existence of a reservoir(s) of antibiotic resistant bacteria and antibiotic resistance genes in an interactive environment of animals, plants, and humans provides the opportunity for further transfer and dissemination of antibiotic resistance. The emergence of antibiotic resistant bacteria has created growing concern about its impact on animal and human health. To specifically address the impact of antibiotic resistance resulting from the use of antibiotics in agriculture, the American Academy of Microbiology convened a colloquium, “Antibiotic Resistance and the Role of Antimicrobials in Agriculture: A Critical Scientific Assessment,” in Santa Fe, New Mexico, November 2–4, 2001. Colloquium participants included academic, industrial, and government researchers with a wide range of expertise, including veterinary medicine, microbiology, food science, pharmacology, and ecology. These scientists were asked to provide their expert opinions on the current status of antibiotic usage and antibiotic resistance, current research information, and provide recommendations for future research needs. The research areas to be addressed were roughly categorized under the following areas: ▪ Origins and reservoirs of resistance; ▪ Transfer of resistance; ▪ Overcoming/modulating resistance by altering usage; and ▪ Interrupting transfer of resistance. The consensus of colloquium participants was that the evaluation of antibiotic usage and its impact were complex and subject to much speculation and polarization. Part of the complexity stems from the diverse array of animals and production practices for food animal production. The overwhelming consensus was that any use of antibiotics creates the possibility for the development of antibiotic resistance, and that there already exist pools of antibiotic resistance genes and antibiotic resistant bacteria. Much discussion revolved around the measurement of antibiotic usage, the measurement of antibiotic resistance, and the ability to evaluate the impact of various types of usage (animal, human) on overall antibiotic resistance. Additionally, many participants identified commensal bacteria as having a possible role in the continuance of antibiotic resistance as reservoirs. Participants agreed that many of the research questions could not be answered completely because of their complexity and the need for better technologies. The concept of the “smoking gun” to indicate that a specific animal source was important in the emergence of certain antibiotic resistant pathogens was discussed, and it was agreed that ascribing ultimate responsibility is likely to be impossible. There was agreement that expanded and more improved surveillance would add to current knowledge. Science-based risk assessments would provide better direction in the future. As far as preventive or intervention activities, colloquium participants reiterated the need for judicious/prudent use guidelines. Yet they also emphasized the need for better dissemination and incorporation by end-users. It is essential that there are studies to measure the impact of educational efforts on antibiotic usage. Other recommendations included alternatives to antibiotics, such as commonly mentioned vaccines and probiotics. There also was an emphasis on management or production practices that might decrease the need for antibiotics. Participants also stressed the need to train new researchers and to interest students in postdoctoral work, through training grants, periodic workshops, and comprehensive conferences. This would provide the expertise needed to address these difficult issues in the future. Finally, the participants noted that scientific societies and professional organizations should play a pivotal role in providing technical advice, distilling and disseminating information to scientists, media, and consumers, and in increasing the visibility and funding for these important issues. The overall conclusion is that antibiotic resistance remains a complex issue with no simple answers. This reinforces the messages from other meetings. The recommendations from this colloquium provide some insightful directions for future research and action.200232687288
884670.9614Phage Resistance Accompanies Reduced Fitness of Uropathogenic Escherichia coli in the Urinary Environment. Urinary tract infection (UTI) is among the most common infections treated worldwide each year and is caused primarily by uropathogenic Escherichia coli (UPEC). Rising rates of antibiotic resistance among uropathogens have spurred a consideration of alternative treatment strategies, such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, namely, HP3 and ES17, against clinical UPEC isolates using in vitro and in vivo models of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6 to 8 h of coincubation. Whole-genome sequencing revealed that UPEC strains resistant to HP3 and ES17 harbored mutations in genes involved in lipopolysaccharide (LPS) biosynthesis. Phage-resistant strains displayed several in vitro phenotypes, including alterations to adherence to and invasion of human bladder epithelial HTB-9 cells and increased biofilm formation in some isolates. Interestingly, these phage-resistant UPEC isolates demonstrated reduced growth in pooled human urine, which could be partially rescued by nutrient supplementation and were more sensitive to several outer membrane-targeting antibiotics than parental strains. Additionally, phage-resistant UPEC isolates were attenuated in bladder colonization in a murine UTI model. In total, our findings suggest that while resistance to phages, such as HP3 and ES17, may arise readily in the urinary environment, phage resistance is accompanied by fitness costs which may render UPEC more susceptible to host immunity or antibiotics. IMPORTANCE UTI is one of the most common causes of outpatient antibiotic use, and rising antibiotic resistance threatens the ability to control UTI unless alternative treatments are developed. Bacteriophage (phage) therapy is gaining renewed interest; however, much like with antibiotics, bacteria can readily become resistant to phages. For successful UTI treatment, we must predict how bacteria will evade killing by phage and identify the downstream consequences of phage resistance during bacterial infection. In our current study, we found that while phage-resistant bacteria quickly emerged in vitro, these bacteria were less capable of growing in human urine and colonizing the murine bladder. These results suggest that phage therapy poses a viable UTI treatment if phage resistance confers fitness costs for the uropathogen. These results have implications for developing cocktails of phage with multiple different bacterial targets, of which each is evaded only at the cost of bacterial fitness.202235920561
902780.9614Scorpion Venom Antimicrobial Peptides Induce Siderophore Biosynthesis and Oxidative Stress Responses in Escherichia coli. The increasing development of microbial resistance to classical antimicrobial agents has led to the search for novel antimicrobials. Antimicrobial peptides (AMPs) derived from scorpion and snake venoms offer an attractive source for the development of novel therapeutics. Smp24 (24 amino acids [aa]) and Smp43 (43 aa) are broad-spectrum AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio mauruspalmatus and subsequently characterized. Using a DNA microarray approach, we examined the transcriptomic responses of Escherichia coli to subinhibitory concentrations of Smp24 and Smp43 peptides following 5 h of incubation. Seventy-two genes were downregulated by Smp24, and 79 genes were downregulated by Smp43. Of these genes, 14 genes were downregulated in common and were associated with bacterial respiration. Fifty-two genes were specifically upregulated by Smp24. These genes were predominantly related to cation transport, particularly iron transport. Three diverse genes were independently upregulated by Smp43. Strains with knockouts of differentially regulated genes were screened to assess the effect on susceptibility to Smp peptides. Ten mutants in the knockout library had increased levels of resistance to Smp24. These genes were predominantly associated with cation transport and binding. Two mutants increased resistance to Smp43. There was no cross-resistance in mutants resistant to Smp24 or Smp43. Five mutants showed increased susceptibility to Smp24, and seven mutants showed increased susceptibility to Smp43. Of these mutants, formate dehydrogenase knockout (fdnG) resulted in increased susceptibility to both peptides. While the electrostatic association between pore-forming AMPs and bacterial membranes followed by integration of the peptide into the membrane is the initial starting point, it is clear that there are numerous subsequent additional intracellular mechanisms that contribute to their overall antimicrobial effect.IMPORTANCE The development of life-threatening resistance of pathogenic bacteria to the antibiotics typically in use in hospitals and the community today has led to an urgent need to discover novel antimicrobial agents with different mechanisms of action. As an ancient host defense mechanism of the innate immune system, antimicrobial peptides (AMPs) are attractive candidates to fill that role. Scorpion venoms have proven to be a rich source of AMPs. Smp24 and Smp43 are new AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio maurus palmatus, and these peptides can kill a wide range of bacterial pathogens. By better understanding how these AMPs affect bacterial cells, we can modify their structure to make better drugs in the future.202133980680
517390.9614Screening of genes involved in phage-resistance of Escherichia coli and effects of substances interacting with primosomal protein A on the resistant bacteria. AIMS: The study was to identify the genes involved in phage resistance and to develop an effective biocontrol method to improve the lytic activity of phages against foodborne pathogens. METHODS AND RESULTS: A total of 3,909 single gene-deletion mutants of Escherichia coli BW25113 from the Keio collection were individually screened for genes involved in phage resistance. Phage S127BCL3 isolated from chicken liver, infecting both E. coli BW25113 and O157: H7, was characterized and used for screening. The 10 gene-deletion mutants showed increased susceptibility to phage S127BCL3. Among them, priA gene-deletion mutant strain showed significant susceptibility to the phages S127BCL3 and T7. Furthermore, we investigated the substances that have been reported to inhibit the function of primosomal protein A (PriA) and were used to confirm increased phage susceptibility in E. coli BW25113 (Parent strain) and O157: H7. CONCLUSION: PriA inhibitors at a low concentration showed combined effects with phage against E. coli O157: H7 and delayed the regrowth rate of phage-resistant cells.202438142224
8134100.9613Sweet scents from good bacteria: Case studies on bacterial volatile compounds for plant growth and immunity. Beneficial bacteria produce diverse chemical compounds that affect the behavior of other organisms including plants. Bacterial volatile compounds (BVCs) contribute to triggering plant immunity and promoting plant growth. Previous studies investigated changes in plant physiology caused by in vitro application of the identified volatile compounds or the BVC-emitting bacteria. This review collates new information on BVC-mediated plant-bacteria airborne interactions, addresses unresolved questions about the biological relevance of BVCs, and summarizes data on recently identified BVCs that improve plant growth or protection. Recent explorations of bacterial metabolic engineering to alter BVC production using heterologous or endogenous genes are introduced. Molecular genetic approaches can expand the BVC repertoire of beneficial bacteria to target additional beneficial effects, or simply boost the production level of naturally occurring BVCs. The effects of direct BVC application in soil are reviewed and evaluated for potential large-scale field and agricultural applications. Our review of recent BVC data indicates that BVCs have great potential to serve as effective biostimulants and bioprotectants even under open-field conditions.201626177913
9085110.9612Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink. While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed.201626802120
9813120.9610Antibacterial Discovery: 21st Century Challenges. It has been nearly 50 years since the golden age of antibiotic discovery (1945-1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.202032353943
9734130.9609Combination of genetically diverse Pseudomonas phages enhances the cocktail efficiency against bacteria. Phage treatment has been used as an alternative to antibiotics since the early 1900s. However, bacteria may acquire phage resistance quickly, limiting the use of phage treatment. The combination of genetically diverse phages displaying distinct replication machinery in phage cocktails has therefore become a novel strategy to improve therapeutic outcomes. Here, we isolated and studied lytic phages (SPA01 and SPA05) that infect a wide range of clinical Pseudomonas aeruginosa isolates. These relatively small myophages have around 93 kbp genomes with no undesirable genes, have a 30-min latent period, and reproduce a relatively high number of progenies, ranging from 218 to 240 PFU per infected cell. Even though both phages lyse their hosts within 4 h, phage-resistant bacteria emerge during the treatment. Considering SPA01-resistant bacteria cross-resist phage SPA05 and vice versa, combining SPA01 and SPA05 for a cocktail would be ineffective. According to the decreased adsorption rate of the phages in the resistant isolates, one of the anti-phage mechanisms may occur through modification of phage receptors on the target cells. All resistant isolates, however, are susceptible to nucleus-forming jumbophages (PhiKZ and PhiPA3), which are genetically distinct from phages SPA01 and SPA05, suggesting that the jumbophages recognize a different receptor during phage entry. The combination of these phages with the jumbophage PhiKZ outperforms other tested combinations in terms of bactericidal activity and effectively suppresses the emergence of phage resistance. This finding reveals the effectiveness of the diverse phage-composed cocktail for reducing bacterial growth and prolonging the evolution of phage resistance.202337264114
9437140.9607Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants. Control of bacterial diseases has, for many years, been dependent on the use of antibiotics. Due to the high levels of efficacy of antibiotics in the past other disease control options have, to a large extent, been neglected. Mankind is now facing an increasing problem with antibiotic resistance. In an effort to retain some antibiotics for human use, there are moves afoot to limit or even ban the use of antibiotics in animal production. The use of antibiotics as growth promoters have been banned in the European Union and the USA. The potential ban on the use of antibiotics to treat diseases in production animals creates a dilemma for man-suffer significant problem with bacterial infection or suffer from a severe shortage of food! There are other options for the control of bacterial diseases. These include vaccine development, bacteriophage therapy, and improved biosecurity. Vaccine development against bacterial pathogens, particularly opportunistic pathogens, is often very challenging, as in many cases the molecular basis of the virulence is not always clearly understood. This is particularly true for Escherichia coli. Biosecurity (disinfection) has been a highly neglected area in disease control. With the ever-increasing problems with antibiotic resistance-the focus should return to improvements in biosecurity. As with antibiotics, bacteria also have mechanisms for resistance to disinfectants. To ensure that we do not replace one set of problems (increasing antibiotic resistance) with another (increasing resistance to disinfectants) we need to fully understand the modes of action of disinfectants and how the bacteria develop resistance to these disinfectants. Molecular studies have been undertaken to relate the presence of QAC resistance genes in bacteria to their levels of sensitivity to different generations of QAC-based products. The mode of action of QAC on bacteria has been studied using NanoSAM technology, where it was revealed that the QAC causes disruption of the bacterial cell wall and leaking of the cytoplasm out of the cells. Our main focus is on the control of bacterial and viral diseases in the poultry industry in a post-antibiotic era, but the principles remain similar for disease control in any veterinary field as well as in human medicine.201424595606
6648150.9606Multi-Drug Resistant Coliform: Water Sanitary Standards and Health Hazards. Water constitutes and sustains life; however, its pollution afflicts its necessity, further worsening its scarcity. Coliform is one of the largest groups of bacteria evident in fecally polluted water, a major public health concern. Coliform thrive as commensals in the gut of warm-blooded animals, and are indefinitely passed through their feces into the environment. They are also called as model organisms as their presence is indicative of the prevalence of other potential pathogens, thus coliform are and unanimously employed as adept indicators of fecal pollution. As only a limited accessible source of fresh water is available on the planet, its contamination severely affects its usability. Coliform densities vary geographically and seasonally which leads to the lack of universally uniform regulatory guidelines regarding water potability often leads to ineffective detection of these model organisms and the misinterpretation of water quality status. Remedial measures such as disinfection, reducing the nutrient concentration or re-population doesn't hold context in huge lotic ecosystems such as freshwater rivers. There is also an escalating concern regarding the prevalence of multi-drug resistance in coliforms which renders antibiotic therapy incompetent. Antimicrobials are increasingly used in household, clinical, veterinary, animal husbandry and agricultural settings. Sub-optimal concentrations of these antimicrobials are unintentionally but regularly dispensed into the environment through seepages, sewages or runoffs from clinical or agricultural settings substantially adding to the ever-increasing pool of antibiotic resistance genes. When present below their minimum inhibitory concentration (MIC), these antimicrobials trigger the transfer of antibiotic-resistant genes that the coliform readily assimilate and further propagate to pathogens, the severity of which is evidenced by the high Multiple Antibiotic Resistance (MAR) index shown by the bacterial isolates procured from the environmental. This review attempts to assiduously anthologize the use of coliforms as water quality standards, their existent methods of detection and the issue of arising multi-drug resistance in them.201829946253
6650160.9606 Antibiotic resistance is never going to go away. No matter how many drugs we throw at it, no matter how much money and resources are sacrificed to wage a war on resistance, it will always prevail. Humans are forced to coexist with the fact of antibiotic resistance. Public health officials, clinicians, and scientists must find effective ways to cope with antibiotic resistant bacteria harmful to humans and animals and to control the development of new types of resistance. The American Academy of Microbiology convened a colloquium October 12–14, 2008, to discuss antibiotic resistance and the factors that influence the development and spread of resistance. Participants, whose areas of expertise included medicine, microbiology, and public health, made specific recommendations for needed research, policy development, a surveillance network, and treatment guidelines. Antibiotic resistance issues specific to the developing world were discussed and recommendations for improvements were made. Each antibiotic is injurious only to a certain segment of the microbial world, so for a given antibacterial there are some species of bacteria that are susceptible and others not. Bacterial species insusceptible to a particular drug are “naturally resistant.” Species that were once sensitive but eventually became resistant to it are said to have “acquired resistance.” It is important to note that “acquired resistance” affects a subset of strains in the entire species; that is why the prevalence of “acquired resistance” in a species is different according to location. Antibiotic resistance, the acquired ability of a pathogen to withstand an antibiotic that kills off its sensitive counterparts, originally arises from random mutations in existing genes or from intact genes that already serve a similar purpose. Exposure to antibiotics and other antimicrobial products, whether in the human body, in animals, or the environment, applies selective pressure that encourages resistance to emerge favoring both “naturally resistant” strains and strains which have “acquired resistance.” Horizontal gene transfer, in which genetic information is passed between microbes, allows resistance determinants to spread within harmless environmental or commensal microorganisms and pathogens, thus creating a reservoir of resistance. Resistance is also spread by the replication of microbes that carry resistance genes, a process that produces genetically identical (or clonal) progeny. Rapid diagnostic methods and surveillance are some of the most valuable tools in preventing the spread of resistance. Access to more rapid diagnostic tests that could determine the causative agent and antibiotic susceptibility of infections would inform better decision making with respect to antibiotic use, help slow the selection of resistant strains in clinical settings, and enable better disease surveillance. A rigorous surveillance network to track the evolution and spread of resistance is also needed and would probably result in significant savings in healthcare. Developing countries face unique challenges when it comes to antibiotic resistance; chief among them may be the wide availability of antibiotics without a prescription and also counterfeit products of dubious quality. Lack of adequate hygiene, poor water quality, and failure to manage human waste also top the list. Recommendations for addressing the problems of widespread resistance in the developing world include: proposals for training and infrastructure capacity building; surveillance programs; greater access to susceptibility testing; government controls on import, manufacture and use; development and use of vaccines; and incentives for pharmaceutical companies to supply drugs to these countries. Controlling antibiotic resistant bacteria and subsequent infections more efficiently necessitates the prudent and responsible use of antibiotics. It is mandatory to prevent the needless use of antibiotics (e.g., viral infections; unnecessary prolonged treatment) and to improve the rapid prescription of appropriate antibiotics to a patient. Delayed or inadequate prescriptions reduce the efficacy of treatment and favor the spread of the infection. Prudent use also applies to veterinary medicine. For example, antibiotics used as “growth promoters” have been banned in Europe and are subject to review in some other countries. There are proven techniques for limiting the spread of resistance, including hand hygiene, but more rapid screening techniques are needed in order to effectively track and prevent spread in clinical settings. The spread of antibiotic resistance on farms and in veterinary hospitals may also be significant and should not be neglected. Research is needed to pursue alternative approaches, including vaccines, antisense therapy, public health initiatives, and others. The important messages about antibiotic resistance are not getting across from scientists and infectious diseases specialists to prescribers, stakeholders, including the public, healthcare providers, and public officials. Innovative and effective communication initiatives are needed, as are carefully tailored messages for each of the stakeholder groups.200932644325
9086170.9604Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas. Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas. We integrate spatio-temporal host immunity, INH and RIF dynamics, and bacterial dynamics (including fitness costs and compensatory mutations) in a computational framework. We simulate resistance emergence in the absence of treatment, as well as resistance selection during INH and/or RIF treatment. There are four main findings. First, in the absence of treatment, the percentage of granulomas containing resistant bacteria mirrors the non-monotonic bacterial dynamics within granulomas. Second, drug-resistant bacteria are less frequently found in non-replicating states in caseum, compared to drug-sensitive bacteria. Third, due to a steeper dose response curve and faster plasma clearance of INH compared to RIF, INH-resistant bacteria have a stronger influence on treatment outcomes than RIF-resistant bacteria. Finally, under combination therapy with INH and RIF, few MDR bacteria are able to significantly affect treatment outcomes. Overall, our approach allows drug-specific prediction of drug resistance emergence and selection in the complex granuloma context. Since our predictions are based on pre-clinical data, our approach can be implemented relatively early in the treatment development process, thereby enabling pro-active rather than reactive responses to emerging drug resistance for new drugs. Furthermore, this quantitative and drug-specific approach can help identify drug-specific properties that influence resistance and use this information to design treatment regimens that minimize resistance selection and expand the useful life-span of new antibiotics.201829746491
9014180.9604Role of acid responsive genes in the susceptibility of Escherichia coli to ciclopirox. Antibiotic resistance poses a huge threat to the effective treatment of bacterial infections. To circumvent the limitations in developing new antibiotics, researchers are attempting to repurpose pre-developed drugs that are known to be safe. Ciclopirox, an off-patent antifungal agent, inhibits the growth of Gram-negative bacteria, and genes involved in galactose metabolism and lipopolysaccharide (LPS) biosynthesis are plausible antibacterial targets for ciclopirox, since their expression levels partially increase susceptibility at restrictive concentrations. In the present study, to identify new target genes involved in the susceptibility of Escherichia coli to ciclopirox, genome-wide mRNA profiling was performed following ciclopirox addition at sublethal concentrations, and glutamate-dependent acid resistance (GDAR) genes were differentially regulated. Additional susceptibility testing, growth analyses and viability assays of GDAR regulatory genes revealed that down-regulation of evgS or hns strongly enhanced susceptibility to ciclopirox. Further microscopy and phenotypic analyses revealed that down-regulation of these genes increased cell size and decreased motility. Our findings could help to maximise the efficacy of ciclopirox against hard-to-treat Gram-negative pathogens.201829654752
5168190.9604Bacteriophage Resistance Affects Flavobacterium columnare Virulence Partly via Mutations in Genes Related to Gliding Motility and the Type IX Secretion System. Increasing problems with antibiotic resistance have directed interest toward phage therapy in the aquaculture industry. However, phage resistance evolving in target bacteria is considered a challenge. To investigate how phage resistance influences the fish pathogen Flavobacterium columnare, two wild-type bacterial isolates, FCO-F2 and FCO-F9, were exposed to phages (FCO-F2 to FCOV-F2, FCOV-F5, and FCOV-F25, and FCO-F9 to FCL-2, FCOV-F13, and FCOV-F45), and resulting phenotypic and genetic changes in bacteria were analyzed. Bacterial viability first decreased in the exposure cultures but started to increase after 1 to 2 days, along with a change in colony morphology from original rhizoid to rough, leading to 98% prevalence of the rough morphotype. Twenty-four isolates (including four isolates from no-phage treatments) were further characterized for phage resistance, antibiotic susceptibility, motility, adhesion, and biofilm formation, protease activity, whole-genome sequencing, and virulence in rainbow trout fry. The rough isolates arising in phage exposure were phage resistant with low virulence, whereas rhizoid isolates maintained phage susceptibility and high virulence. Gliding motility and protease activity were also related to the phage susceptibility. Observed mutations in phage-resistant isolates were mostly located in genes encoding the type IX secretion system, a component of the Bacteroidetes gliding motility machinery. However, not all phage-resistant isolates had mutations, indicating that phage resistance in F. columnare is a multifactorial process, including both genetic mutations and changes in gene expression. Phage resistance may not, however, be a challenge for development of phage therapy against F. columnare infections since phage resistance is associated with decreases in bacterial virulence. IMPORTANCE Phage resistance of infectious bacteria is a common phenomenon posing challenges for the development of phage therapy. Along with a growing world population and the need for increased food production, constantly intensifying animal farming has to face increasing problems of infectious diseases. Columnaris disease, caused by Flavobacterium columnare, is a worldwide threat for salmonid fry and juvenile farming. Without antibiotic treatments, infections can lead to 100% mortality in a fish stock. Phage therapy of columnaris disease would reduce the development of antibiotic-resistant bacteria and antibiotic loads by the aquaculture industry, but phage-resistant bacterial isolates may become a risk. However, phenotypic and genetic characterization of phage-resistant F. columnare isolates in this study revealed that they are less virulent than phage-susceptible isolates and thus not a challenge for phage therapy against columnaris disease. This is valuable information for the fish farming industry globally when considering phage-based prevention and curing methods for F. columnare infections.202134106011