# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9733 | 0 | 1.0000 | The 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. | 2018 | 30351434 |
| 9813 | 1 | 0.9991 | Antibacterial 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. | 2020 | 32353943 |
| 9899 | 2 | 0.9990 | Evolution of extended-spectrum beta-lactamases by mutation. Antimicrobial resistance genes in pathogenic bacteria belong to the most rapidly evolving DNA sequences, which results in an enormous structural diversity of resistance effectors. Structural modifications of resistance genes by mutation and recombination, together with a multitude of events that stimulate their mobility and expression, allow microorganisms to survive in environments saturated with antimicrobial agents of various types and generations. Genes coding for beta-lactamases in Gram-negative bacteria are a fascinating example of this multifocal and multidirectional evolution, with the extended-spectrum beta-lactamases (ESBLs) being one of the most spectacular 'achievements'. Some of the ESBLs known today are 'ready-to-use' enzymes in their natural producers but these are often of low pathogenic potential, or none at all. The problem appears upon mobilisation of a gene encoding such an ESBL, and its acquisition and sufficient expression by a more virulent organism. Many ESBLs are generated by mutations in genes coding for broad-spectrum enzymes, which have been mobile since at least the 1960s and which have disseminated very widely in populations of pathogenic bacteria. Strong selection pressure exerted by antimicrobial use, especially with newer-generation beta-lactam antibiotics, efficiently promotes these two modes of ESBL emergence and subsequent spread. It also stimulates further evolution of ESBLs by accumulation of other mutations with an astonishing variety of effects on beta-lactamase structure and activity. Remarkably, more than 300 natural ESBL variants have been identified since the mid-1980s but in-vitro studies suggest that ESBL evolution has certainly not come to an end; they may also help in predicting future developments. The aim of this review is to briefly overview the role of various mutations in ESBL evolution. | 2008 | 18154525 |
| 9610 | 3 | 0.9990 | The evolutionary rate of antibacterial drug targets. BACKGROUND: One of the major issues in the fight against infectious diseases is the notable increase in multiple drug resistance in pathogenic species. For that reason, newly acquired high-throughput data on virulent microbial agents attract the attention of many researchers seeking potential new drug targets. Many approaches have been used to evaluate proteins from infectious pathogens, including, but not limited to, similarity analysis, reverse docking, statistical 3D structure analysis, machine learning, topological properties of interaction networks or a combination of the aforementioned methods. From a biological perspective, most essential proteins (knockout lethal for bacteria) or highly conserved proteins (broad spectrum activity) are potential drug targets. Ribosomal proteins comprise such an example. Many of them are well-known drug targets in bacteria. It is intuitive that we should learn from nature how to design good drugs. Firstly, known antibiotics are mainly originating from natural products of microorganisms targeting other microorganisms. Secondly, paleontological data suggests that antibiotics have been used by microorganisms for million years. Thus, we have hypothesized that good drug targets are evolutionary constrained and are subject of evolutionary selection. This means that mutations in such proteins are deleterious and removed by selection, which makes them less susceptible to random development of resistance. Analysis of the speed of evolution seems to be good approach to test this hypothesis. RESULTS: In this study we show that pN/pS ratio of genes coding for known drug targets is significantly lower than the genome average and also lower than that for essential genes identified by experimental methods. Similar results are observed in the case of dN/dS analysis. Both analyzes suggest that drug targets tend to evolve slowly and that the rate of evolution is a better predictor of drugability than essentiality. CONCLUSIONS: Evolutionary rate can be used to score and find potential drug targets. The results presented here may become a useful addition to a repertoire of drug target prediction methods. As a proof of concept, we analyzed GO enrichment among the slowest evolving genes. These may become the starting point in the search for antibiotics with a novel mechanism. | 2013 | 23374913 |
| 4248 | 4 | 0.9990 | Phage Display Technique: A Novel Medicinal Approach to Overcome An tibiotic Resistance by Using Peptide-Based Inhibitors Against β-Lactamases. The emergence of antibiotic resistance in bacteria is a serious threat with enormous social and economic implications. The distribution of resistance genes/markers through horizontal gene transfer leads to the dissemination of resistant strains in different parts of the world. The resistant bacteria acquire the ability to overcome resistance by different modes amongst which the expression of β-lactamases is a major factor. The β-lactamase enzymes cleave the amide bond of the β-lactam antibiotics, which constitute about one-third of the antibiotics used all over the world. In a quest to control the spread of resistant bacteria, advanced generations of antibiotics are used either alone or in combination with inhibitors. However, these antibiotics and inhibitors also contain β-lactam ring in their structure and hence are prone to be hydrolyzed by β-lactamase enzymes in the near future. Thus, the severity of the problem is manifested due to the paucity of novel non-β-lactam core containing antibiotics in the drug development stage. One approach to overcome these shortcomings is to use peptide-based inhibitors. Here, we describe the potential use of phage display technique to screen commercially available libraries to pan against β-lactamase enzymes. The main advantage of using peptide-based inhibitors is that the bacteria will not be able to recruit pre-existing defense mechanisms and it will take a long time to evolve a new mechanism in its defense against peptide-based inhibitors. | 2017 | 27465983 |
| 9572 | 5 | 0.9990 | Diagnostic Evasion of Highly-Resistant Microorganisms: A Critical Factor in Nosocomial Outbreaks. Highly resistant microorganisms (HRMOs) may evade screening strategies used in routine diagnostics. Bacteria that have evolved to evade diagnostic tests may have a selective advantage in the nosocomial environment. Evasion of resistance detection can result from the following mechanisms: low-level expression of resistance genes not resulting in detectable resistance, slow growing variants, mimicry of wild-type-resistance, and resistance mechanisms that are only detected if induced by antibiotic pressure. We reviewed reports on hospital outbreaks in the Netherlands over the past 5 years. Remarkably, many outbreaks including major nation-wide outbreaks were caused by microorganisms able to evade resistance detection by diagnostic screening tests. We describe various examples of diagnostic evasion by several HRMOs and discuss this in a broad and international perspective. The epidemiology of hospital-associated bacteria may strongly be affected by diagnostic screening strategies. This may result in an increasing reservoir of resistance genes in hospital populations that is unnoticed. The resistance elements may horizontally transfer to hosts with systems for high-level expression, resulting in a clinically significant resistance problem. We advise to communicate the identification of HRMOs that evade diagnostics within national and regional networks. Such signaling networks may prevent inter-hospital outbreaks, and allow collaborative development of adapted diagnostic tests. | 2017 | 29163416 |
| 4280 | 6 | 0.9989 | Droplet Microfluidics for High-Throughput Analysis of Antibiotic Susceptibility in Bacterial Cells and Populations. Antibiotic-resistant bacteria are an increasing concern both in everyday life and specialized environments such as healthcare. As the rate of antibiotic-resistant infections rises, so do complications to health and the risk of disability and death. Urgent action is required regarding the discovery of new antibiotics and rapid diagnosis of the resistance profile of an infectious pathogen as well as a better understanding of population and single-cell distribution of the resistance level. High-throughput screening is the major affordance of droplet microfluidics. Droplet screens can be exploited both to look for combinations of drugs that could stop an infection of multidrug-resistant bacteria and to search for the source of resistance via directed-evolution experiments or the analysis of various responses to a drug by genetically identical bacteria. In droplet techniques that have been used in this way for over a decade, aqueous droplets containing antibiotics and bacteria are manipulated both within and outside of the microfluidic devices. The diagnostics problem was approached by producing a series of microfluidic systems with integrated dilution modules for automated preparation of antibiotic concentration gradients, achieving the speed that allowed for high-throughput combinatorial assays. We developed a method for automated emulsification of a series of samples that facilitated measuring the resistance levels of thousands of individual cells encapsulated in droplets and quantifying the inoculum effect, the dependence of resistance level on bacterial cell count. Screening of single cells encapsulated in droplets with varying antibiotic contents has revealed a distribution of resistance levels within populations of clonally identical cells. To be able to screen bacteria from clinical samples, a study of fluorescent dyes in droplets determined that a derivative of a popular viability marker is more suitable for droplet assays. We have developed a detection system that analyzes the growth or death state of bacteria with antibiotics for thousands of droplets per second by measuring the scattering of light hitting the droplets without labeling the cells or droplets. The droplet-based microchemostats enabled long-term evolution of resistance experiments, which will be integrated with high-throughput single-cell assays to better understand the mechanism of resistance acquisition and loss. These techniques underlie automated combinatorial screens of antibiotic resistance in single cells from clinical samples. We hope that this Account will inspire new droplet-based research on the antibiotic susceptibility of bacteria. | 2022 | 35119826 |
| 4329 | 7 | 0.9989 | Bacterial resistance: new threats, new challenges. Bacterial resistance remains a major concern. Recently, genetic transfers from saprophytic, non-pathogenic, species to pathogenic S. pneumoniae and N. meningitidis have introduced multiple changes in the penicillin target molecules, leading to rapidly growing penicillin resistance. In enterobacteriaceae, a succession of minute mutations has generated new beta-lactamases with increasingly expanded spectrum, now covering practically all available beta-lactam antibiotics. Resistance emerges in the hospital environment but also, and increasingly, in the community bacteria. Widespread resistance is probably associated with antibiotic use, abuse and misuse but direct causality links are difficult to establish. In some countries as in some hospitals, unusual resistance profiles seem to correspond to unusual antibiotic practices. For meeting the resistance challenge, no simple solutions are available, but combined efforts may help. For improving the situation, the following methods can be proposed. At the world level, a better definition of appropriate antibiotic policies should be sought, together with strong education programmes on the use of antibiotics and the control of cross-infections, plus controls on the strategies used by pharmaceutical companies for promoting antibiotics. At various local levels, accurate guidelines should be adapted to each institution and there should be regularly updated formularies using scientific, and not only economic, criteria; molecular technologies for detecting subtle epidemic variations and emergence of new genes should be developed and regular information on the resistance profiles should be available to all physicians involved in the prevention and therapy of infections. | 1993 | 8149138 |
| 4237 | 8 | 0.9989 | Antibiotics: action and resistance in gram-negative bacteria. Therapeutic control of beta-lactamase-producing bacteria has been a major clinical problem in the past 40 years. Gram-negative bacteria are most often resistant to antibiotics as a result of the acquisition of resistant genes or gene mutation. Studies have shown that newly developed antibiotics will shortly fail to be active against the bacteria because of the emergence of resistance. Some resistant bacteria have been found to exist even before the antibiotic was developed. Selective pressure by the antibiotic is, therefore, one of the major factors to explain the increase of resistance. Recently, numerous resistant mechanisms that differ in their substrate profiles have been described at increasing frequencies. The inappropriate use of new antibiotics with extended spectrum further complicated the problem. Because resistance is a largely unavoidable consequence of widespread use of antibiotics, it is crucial that the use of drugs is selective by exercising prudent judgment and not excessive. The actual prevalence of resistance should be continuously monitored each year. Caution should be paid to the direct extrapolation of study results from other geographic areas, because the local prevalence of resistance is unlikely to be identical to those reported elsewhere. The impact of resistance to an antibiotic and its specific mechanisms, including transmissibility, should also be carefully studied. Such information may help in designing strategies for maximizing the therapeutic usefulness of drugs and minimizing the emergence of resistance. | 2002 | 11950113 |
| 9570 | 9 | 0.9989 | Antibiotic use in developing countries. Antimicrobials have been used successfully for over 6 decades, but genes expressing resistance to them have emerged in strains of bacteria and have disseminated through the global ecosystem to reach infecting microorganisms, produce disease, and seriously interfere with therapy, allowing infections to progress and kill despite antibiotic administration. The upsurge in prevalence of such resistance genes in the bacterial population that colonize and infect humans involves two processes, emergence and dissemination, in both of which there have been contributions from the developing world, where resistance is common and increasing. The emergence of pneumococcal isolates noted in Papua New Guinea and later in South Africa that 1 decade later spread to most of the world and the intercontinental spread between the United States and Venezuela of a new gentamicin resistance gene carried on an epidemic plasmid are examples of the ability of bacteria to travel freely, without regard to borders. Complex societal issues such as the misuse of antibiotics by physicians, pharmacists, and the public; the suboptimal quality of the drugs (emergence); and conditions such as crowding, lack of hygiene, poor or nonexistent hospital infection control practices, or insufficient surveillance (dissemination) play a largely unmeasured role that requires study and solutions. In the meantime, we may intervene to delay the emergence of resistance and to limit its spread by promoting the judicious use of antibiotics both at the local level as well as from multinational organized cooperative efforts. Education and improvement of surveillance and socioeconomic conditions are integral parts of any solution strategy. | 2000 | 10879571 |
| 4330 | 10 | 0.9989 | Decolonization of asymptomatic carriage of multi-drug resistant bacteria by bacteriophages? Antimicrobial resistance is a major threat to human and animal health and accounted for up to 4.5 million deaths worldwide in 2019. Asymptomatic colonization of the digestive tract by multidrug resistant (multi-resistant) bacteria such as extended-spectrum beta-lactamase-, or carbapenemase- producing Enterobacterales is (i) a risk factor for infection by these multi-resistant bacteria, (ii) a risk factor of dissemination of these multi-resistant bacteria among patients and in the community, and (iii) allows the exchange of resistance genes between bacteria. Hence, decolonization or reduction of the gastrointestinal tract colonization of these multi-resistant bacteria needs to be urgently explored. Developing new non-antibiotic strategies to limit or eradicate multi-resistant bacteria carriage without globally disrupting the microbiota is considered a priority to fight against antibiotic resistance. Probiotics or Fecal Microbiota Transplantation are alternative strategies to antibiotics that have been considered to decolonize intestinal tract from MDR bacteria but there is currently no evidence demonstrating their efficacy. Lytic bacteriophages are viruses that kill bacteria and therefore could be considered as a promising strategy to combat antibiotic resistance. Successful decolonization by bacteriophages has already been observed clinically. Here, we discuss the current alternative strategies considered to decolonize the digestive tract of multidrug resistant bacteria, briefly describing probiotics and fecal microbiota transplantation approaches, and then detail the in vivo and in vitro studies using bacteriophages, while discussing their limits regarding the animal models used, the characteristics of phages used and their activity in regards of the gut anatomy. | 2023 | 38075897 |
| 4883 | 11 | 0.9989 | New tools to mitigate drug resistance in Enterobacteriaceae - Escherichia coli and Klebsiella pneumoniae. Treatment to common bacterial infections are becoming ineffective of late, owing to the emergence and dissemination of antibiotic resistance globally. Escherichia coli and Klebsiella pneumoniae are the most notorious microorganisms and are among the critical priority pathogens listed by WHO in 2017. These pathogens are the predominant cause of sepsis, urinary tract infections (UTIs), pneumonia, meningitis and pyogenic liver abscess. Concern arises due to the resistance of bacteria to most of the beta lactam antibiotics like penicillin, cephalosporin, monobactams and carbapenems, even to the last resort antibiotics like colistin. Preventing influx by modulation of porins, extruding the antibiotics by overexpression of efflux pumps, mutations of drug targets/receptors, biofilm formation, altering the drug molecules and rendering them ineffective are few resistance mechanisms that are adapted by Enterobacteriaeceae upon exposure to antibiotics. The situation is exacerbated due to the process of horizontal gene transfer (HGT), wherein the genes encoding resistance mechanisms are transferred to the neighbouring bacteria through plasmids/phages/uptake of free DNA. Carbapenemases, other beta lactamases and mcr genes coding for colistin resistance are widely disseminated leading to limited/no therapeutic options against those infections. Development of new antibiotics can be viewed as a possible solution but it involves major investment, time and labour despite which, the bacteria can easily adapt to the new antibiotic and evolve resistance in a relatively short time. Targeting the resistance mechanisms can be one feasible alternative to tackle these multidrug resistant (MDR) pathogens. Removal of plasmid (plasmid curing) causing resistance, use of bacteriophages and bacteriotherapy can be other potential approaches to combat infections caused by MDR E. coli and K. pneumoniae. The present review discusses the efficacies of these therapies in mitigating these infections, which can be potentially used as an adjuvant therapy along with existing antibiotics. | 2023 | 35649163 |
| 9462 | 12 | 0.9989 | A bacterial model system for understanding multi-drug resistance. Mankind stands at the crossroads, recognizing the need for a radical change in bacterial disease management. The development of several antimicrobial agents in the 1940s and 1950s allowed man to gain the upper hand in controlling these diseases. However, the horizon is now clouded by the activation in bacteria of cryptic multi-drug resistance (MDR) genes and the spread of plasmid- and integron-born MDR genes through bacterial populations. Unless remedial measures are taken, nearly all currently available antimicrobial agents are likely to soon lose their efficacies. We briefly review the bacterial MDR phenomenon and focus on a recently emerging family of small multi-drug resistance (SMR) pumps which may provide an ideal model system for understanding the MDR phenomenon in general. | 1997 | 9442481 |
| 9920 | 13 | 0.9989 | Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes. The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2], [3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM β-lactamase (bla(TEM)) varied greatly among 15 different β-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles bla(TEM-50) and bla(TEM-85), each of which differs from its ancestor bla(TEM-1) by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV. | 2013 | 23418506 |
| 9438 | 14 | 0.9989 | The challenge of antibiotic resistance: need to contemplate. "Survival of the fittest " holds good for men and animals as also for bacteria. A majority of bacteria in nature are nonpathogenic, a large number of them, live as commensals on our body leading a symbiotic existence. A limited population of bacteria which has became pathogenic was also sensitive to antibiotics to begin with. It is the man made antibiotic pressure, which has led to the emergence and spread of resistant genes amongst bacteria. Despite the availability of a large arsenal of antibiotics, the ability of bacteria to become resistant to antibacterial agents is amazing. This is more evident in the hospital settings where the antibiotic usage is maximum. The use of antibiotics is widespread in clinical medicine, agriculture, aquaculture, veterinary practice, poultry and even in household products. The major reason for this is the inappropriate use of antibiotics due to a lack of uniform policy and disregard to hospital infection control practices. The antibiotic cover provided by newer antibiotics has been an important factor responsible for the emergence of multi-drug resistant bacteria. Bacterial infections increase the morbidity and mortality, increase the cost of treatment, and prolong hospital stay adding to the economical burden on the nation. The problem is further compounded by the lack of education and " over the counter " availability of antibiotics in developing countries. Antibiotic resistance is now all pervasive with the developed world as much vulnerable to the problem. Despite advancement in medical technology for diagnosis and patient care, a person can still die of an infection caused by a multi-drug resistant bacteria. It is time to think, plan and formulate a strong antibiotic policy to address the burgeoning hospital infection. | 2005 | 15756040 |
| 4063 | 15 | 0.9989 | The 2000 Garrod lecture. Factors impacting on the problem of antibiotic resistance. Antibiotic resistance has become a major clinical and public health problem within the lifetime of most people living today. Confronted by increasing amounts of antibiotics over the past 60 years, bacteria have responded to the deluge with the propagation of progeny no longer susceptible to them. While it is clear that antibiotics are pivotal in the selection of bacterial resistance, the spread of resistance genes and of resistant bacteria also contributes to the problem. Selection of resistant forms can occur during or after antimicrobial treatment; antibiotic residues can be found in the environment for long periods of time after treatment. Besides antibiotics, there is the mounting use of other agents aimed at destroying bacteria, namely the surface antibacterials now available in many household products. These too enter the environment. The stage is thus set for an altered microbial ecology, not only in terms of resistant versus susceptible bacteria, but also in terms of the kinds of microorganisms surviving in the treated environment. We currently face multiresistant infectious disease organisms that are difficult and, sometimes, impossible to treat successfully. In order to curb the resistance problem, we must encourage the return of the susceptible commensal flora. They are our best allies in reversing antibiotic resistance. | 2002 | 11751763 |
| 9467 | 16 | 0.9989 | To give or not to give antibiotics is not the only question. In a 1945 Nobel Lecture, Sir Alexander Fleming warned against the overuse of antibiotics, particularly in response to public pressure. In the subsequent decades, evidence has shown that bacteria can become resistant to almost any available molecule. One key question is how the emergence and dissemination of resistant bacteria or resistance genes can be delayed. Although some clinicians remain sceptical, in this Personal View, we argue that the prescription of fewer antibiotics and shorter treatment duration is just as effective as longer regimens that remain the current guideline. Additionally, we discuss the fact that shorter antibiotic treatments exert less selective pressure on microorganisms, preventing the development of resistance. By contrast, longer treatments associated with a strong selective pressure favour the emergence of resistant clones within commensal organisms. We also emphasise that more studies are needed to identify the optimal duration of antibiotic therapy for common infections, which is important for making changes to the current guidelines, and to identify clinical biomarkers to guide antibiotic treatment in both hospital and ambulatory settings. | 2021 | 33347816 |
| 6678 | 17 | 0.9989 | Bacteriophage Therapy to Combat Microbial Infections and Antimicrobial Resistance. Antimicrobial resistance (AMR) is a global issue; however, in lower resource settings, uncontrolled measures and uncontrolled use of antibiotics in human, animal, and agricultural practices have increased their prevalence in developing countries. Various mechanisms have been implicated to explain the AMR, like the circulation of the plasmid carrying antibiotic resistance genes (ARG), mutation in target genes (intrinsic and plasmid), overexpression of efflux pumps, underexpression of porins, etc. Various therapeutic strategies used to combat AMR exist, such as nonantibiotic approaches (vaccinations or immunotherapy, nano-derived treatments, and bacteriophage therapy), Anti-plasmid and plasmid curing approaches, combinatorial approaches (combination of antibiotics as well as a combination of two different approaches), and plant-based therapeutics. In this focused review, we have discussed the potential use of bacteriophage-based therapy to combat AMR and biofilm formation through multifaceted ways, including lysis of the drug-resistant bacteria, targeting the pili of AMR plasmids conjugation systems, and use of phage-derived lytic proteins. Phages can also be used to decontaminate surfaces in healthcare settings, prevent bacterial contamination in food (meat and dairy), and control bacterial populations in environmental settings, such as water and soil. Therefore, the bacteriophages-based approach served as a dual sword and could not only prevent the spread of infectious diseases but also manage the AMR. | 2025 | 40757460 |
| 9520 | 18 | 0.9989 | Role of Natural Product in Modulation of Drug Transporters and New Delhi Metallo-β Lactamases. A rapid growth in drug resistance has brought options for treating antimicrobial resistance to a halt. Bacteria have evolved to accumulate a multitude of genes that encode resistance for a single drug within a single cell. Alternations of drug transporters are one of the causes for the development of resistance in drug interactions. Conversely, the production of enzymes also inactivates most antibiotics. The discovery of newer classes of antibiotics and drugs from natural products is urgently needed. Alternative medicines play an integral role in countries across the globe but many require validation for treatment strategies. It is essential to explore this chemical diversity in order to find novel drugs with specific activities which can be used as alternative drug targets. This review describes the interaction of drugs with resistant pathogens with a special focus on natural product-derived efflux pump and carbapenemase inhibitors. | 2019 | 30987566 |
| 6651 | 19 | 0.9989 | A complex cyclical One Health pathway drives the emergence and dissemination of antimicrobial resistance. Since their commercialization, scientists have known that antimicrobial use kills or inhibits susceptible bacteria while allowing resistant bacteria to survive and expand. Today there is widespread antimicrobial resistance (AMR), even to antimicrobials of last resort such as the carbapenems, which are reserved for use in life-threatening infections. It is often convenient to assign responsibility for this global health crisis to the users and prescribers of antimicrobials. However, we know that animals never treated with antimicrobials carry clinically relevant AMR bacteria and genes. The causal pathway from bacterial susceptibility to resistance is not simple, and dissemination is cyclical rather than linear. Amplification of AMR occurs in healthcare environments and on farms where frequent exposure to antimicrobials selects for resistant bacterial populations. The recipients of antimicrobial therapy release antimicrobial residues, resistant bacteria, and resistance genes in waste products. These are reduced but not removed during wastewater and manure treatment and enter surface waters, soils, recreational parks, wildlife, and fields where animals graze and crops are grown for human and animal consumption. The cycle is complete when a patient carrying AMR bacteria is treated with antimicrobials that amplify the resistant bacterial populations. Reducing the development and spread of AMR requires a One Health approach with the combined commitment of governments, medical and veterinary professionals, agricultural industries, food and feed processors, and environmental scientists. In this review and in the companion Currents in One Health by Ballash et al, JAVMA, April 2024, we highlight just a few of the steps of the complex cyclical causal pathway that leads to the amplification, dissemination, and maintenance of AMR. | 2024 | 38467112 |