CRECC - Word Related Documents




#
Rank
Similarity
Title + Abs.
Year
PMID
012345
600800.8683Photopolymerized 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
843310.8663Thermoresponsive Nanostructures: From Mechano-Bactericidal Action to Bacteria Release. Overuse of antibiotics can increase the risk of notorious antibiotic resistance in bacteria, which has become a growing public health concern worldwide. Featured with the merit of mechanical rupture of bacterial cells, the bioinspired nanopillars are promising alternatives to antibiotics for combating bacterial infections while avoiding antibacterial resistance. However, the resident dead bacterial cells on nanopillars may greatly impair their bactericidal capability and ultimately impede their translational potential toward long-term applications. Here, we show that the functions of bactericidal nanopillars can be significantly broadened by developing a hybrid thermoresponsive polymer@nanopillar-structured surface, which retains all of the attributes of pristine nanopillars and adds one more: releasing dead bacteria. We fabricate this surface through coaxially decorating mechano-bactericidal ZnO nanopillars with thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) brushes. Combining the benefits of ZnO nanopillars and PNIPAAm chains, the antibacterial performances can be controllably regulated between ultrarobust mechano-bactericidal action (∼99%) and remarkable bacteria-releasing efficiency (∼98%). Notably, both the mechanical sterilization against the live bacteria and the controllable release for the pinned dead bacteria solely stem from physical actions, stimulating the exploration of intelligent structure-based bactericidal surfaces with persistent antibacterial properties without the risk of triggering drug resistance.202134905683
975820.8649Study on collateral sensitivity of tigecycline to colistin-resistant Enterobacter cloacae complex. The past decade has witnessed the emergence and spread of carbapenem-resistant Enterobacter cloacae complex (CRECC), presenting a significant clinical challenge and urgently demanding new treatment strategies against antimicrobial resistance (AMR). This study focused on the impact of tigecycline on the susceptibility of CRECC isolates to colistin and the collateral sensitivity in CRECC. Under tigecycline pressure, the resistance of five clinically isolated CRECC strains to colistin was converted from resistance to sensitivity. These mutants exhibited significantly higher expression of acrA, acrB, and ramA genes, with mutations in the ramR gene. Overexpression of ramA in certain mutants did not alter ramR expression. No mutations were identified in lipid A synthesis genes; however, phoQ was consistently downregulated, and arnA expression varied among CRECC405-resistant mutants. Low-dose colistin and tigecycline combination therapy outperformed monotherapy in antimicrobial efficacy. Overall, collateral susceptibility to tigecycline was observed in CRECC isolates with colistin resistance. The overexpression of acrA, acrB, and ramA, due to ramR mutations, led to tigecycline resistance. Inconsistent expression levels of lipid A synthesis genes affected lipid A modification, which in turn upregulated arnA expression in CRECC405-resistant mutants. Increased sensitivity to colistin was associated with the downregulation of phoQ and arnA expression. IMPORTANCE: Antimicrobial resistance (AMR) is escalating faster than our ability to manage bacterial infections, with antibiotic-resistant bacteria emerging as a significant public health risk. Innovative strategies are urgently needed to curb AMR dissemination. Our research identified collateral sensitivity in Enterobacter cloacae complex following tigecycline (TGC) resistance, resulting in newfound sensitivity to colistin (COL), a drug to which it was once resistant. Synergistic tigecycline and colistin therapy significantly suppress bacterial growth, offering a promising approach to combat infections and curb AMR progression through the strategic pairing of antibiotics with complementary sensitivities.202540407373
843730.8629Tocopherol polyethylene glycol succinate-modified hollow silver nanoparticles for combating bacteria-resistance. Multiple drug resistance and the increase in the appearance of superbugs together with the exceedingly scant development of new potent antibiotic drugs pose an urgent global medical threat and imminent public security crisis. In the present study, we fabricated well-dispersed tocopherol polyethylene glycol succinate (TPGS)-capped silver nanoparticles (AgNPs) of about 10 nm in size. The hollow structure of the TPGS-capped AgNPs (TPGS/AgNPs) was confirmed and applied to load antibiotics. The TPGS/AgNPs proved to be able to cross the bacterial cell wall and penetrate into bacteria, thereby delivering more of the antibiotic to the interior of bacteria and thus enhancing the in vitro antibacterial effect of the antibiotic, even overcoming the drug-resistance in drug-resistant E. coli and Acinetobacter baumannii. It was found that the TPGS modification in the TPGS/AgNPs could decrease the activity of the efflux pumps AdeABC and AdeIJK in drug-resistant Acinetobacter baumannii via inhibiting the efflux pump genes adeB and adeJ, thus increasing the accumulation of the delivered antibiotic and overcoming the drug-resistance. Tigecycline delivered by TPGS/AgNPs could effectively antagonize drug-resistance in an acute peritonitis model mice, thereby increasing the survival rate and alleviating the inflammatory response. TPGS/AgNPs were developed as a novel and effective antibiotic delivery system and TPGS was demonstrated to have great potential as a pharmaceutical excipient for use in drug-resistant infection therapy.201930968093
883340.8593"One for All": Functional Transfer of OMV-Mediated Polymyxin B Resistance From Salmonella enterica sv. Typhi ΔtolR and ΔdegS to Susceptible Bacteria. The appearance of multi-resistant strains has contributed to reintroducing polymyxin as the last-line therapy. Although polymyxin resistance is based on bacterial envelope changes, other resistance mechanisms are being reported. Outer membrane vesicles (OMVs) are nanosized proteoliposomes secreted from the outer membrane of Gram-negative bacteria. In some bacteria, OMVs have shown to provide resistance to diverse antimicrobial agents either by sequestering and/or expelling the harmful agent from the bacterial envelope. Nevertheless, the participation of OMVs in polymyxin resistance has not yet been explored in S. Typhi, and neither OMVs derived from hypervesiculating mutants. In this work, we explored whether OMVs produced by the hypervesiculating strains Salmonella Typhi ΔrfaE (LPS synthesis), ΔtolR (bacterial envelope) and ΔdegS (misfolded proteins and σ (E) activation) exhibit protective properties against polymyxin B. We found that the OMVs extracted from S. Typhi ΔtolR and ΔdegS protect S. Typhi WT from polymyxin B in a concentration-depending manner. By contrast, the protective effect exerted by OMVs from S. Typhi WT and S. Typhi ΔrfaE is much lower. This effect is achieved by the sequestration of polymyxin B, as assessed by the more positive Zeta potential of OMVs with polymyxin B and the diminished antibiotic's availability when coincubated with OMVs. We also found that S. Typhi ΔtolR exhibited an increased MIC of polymyxin B. Finally, we determined that S. Typhi ΔtolR and S. Typhi ΔdegS, at a lesser level, can functionally and transiently transfer the OMV-mediated polymyxin B resistance to susceptible bacteria in cocultures. This work shows that mutants in genes related to OMVs biogenesis can release vesicles with improved abilities to protect bacteria against membrane-active agents. Since mutations affecting OMV biogenesis can involve the bacterial envelope, mutants with increased resistance to membrane-acting agents that, in turn, produce protective OMVs with a high vesiculation rate (e.g., S. Typhi ΔtolR) can arise. Such mutants can functionally transfer the resistance to surrounding bacteria via OMVs, diminishing the effective concentration of the antimicrobial agent and potentially favoring the selection of spontaneous resistant strains in the environment. This phenomenon might be considered the source for the emergence of polymyxin resistance in an entire bacterial community.202134025627
908650.8591Emergence 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
873660.8583Effects of intracanal irrigant MTAD Combined with nisin at sub-minimum inhibitory concentration levels on Enterococcus faecalis growth and the expression of pathogenic genes. Exposure to antibiotics is considered to be the major driver in the selection of antibiotic-resistant bacteria and may induce diverse biological responses in bacteria. MTAD is a common intracanal irrigant, but its bactericidal activity remains to be improved. Previous studies have indicated that the antimicrobial peptide nisin can significantly improve the bactericidal activity of MTAD against Enterococcus faecalis. However, the effects of MTAD and its modification at sub-minimum inhibitory concentration (sub-MIC) levels on Enterococcus faecalis growth and the expression of pathogenic genes still need to be explored. In this study, the results of post-antibiotic effects (PAE) and post-antibiotic sub-MIC effects (PASME) showed that MTADN (nisin in combination with MTAD) had the best post-antibiotic effect. E. faecalis after challenge with MTAD was less sensitive to alkaline solutions compared with MTAN (nisin in place of doxycycline in MTAD) and MTADN. E. faecalis induced with sub-MIC of MTAD generated resistance to the higher concentration, but induction of E. faecalis with MTAN did not cause resistance to higher concentrations. Furthermore, real-time polymerase chain reaction (RT-PCR) showed that the stress caused by sub-MIC exposure to MTAD, MTAN, or MTADN resulted in up- or down-regulation of nine stress genes and four virulence-associated genes in E. faecalis and resulted in different stress states. These findings suggested that nisin improved the post-antibacterial effect of MTAD at sub-MIC levels and has considerable potential for use as a modification of MTAD.201424603760
843670.8581NIR-Activated Hydrogel with Dual-Enhanced Antibiotic Effectiveness for Thorough Elimination of Antibiotic-Resistant Bacteria. Antibiotic resistance has become a critical health crisis globally. Traditional strategies using antibiotics can lead to drug-resistance, while inorganic antimicrobial agents can cause severe systemic toxicity. Here, we have developed a dual-antibiotic hydrogel delivery system (PDA-Ag@Levo/CMCS), which can achieve controlled release of clinical antibiotics levofloxacin (Levo) and classic nanoscale antibiotic silver nanoparticles (AgNPs), effectively eliminating drug-resistant P. aeruginosa. Benefiting from the photothermal (PTT) effect of polydopamine (PDA), the local high temperature generated by PDA-Ag@Levo/CMCS can quickly kill bacteria through continuous and responsive release of dual-antibiotics to restore sensitivity to ineffective antibiotics. Moreover, AgNPs could significantly improve the efficiency of traditional antibiotics by disrupting bacterial membranes and reducing their toxicity to healthy tissues. A clever combination of PTT and drug-combination therapy can effectively eliminate biofilms and drug-resistant bacteria. Mechanism studies have shown that PDA-Ag@Levo might eliminate drug-resistant P. aeruginosa by disrupting biofilm formation and protein synthesis, and inhibit the resistance mutation of P. aeruginosa by promoting the expression of related genes, such as rpoS, dinB, and mutS. Collectively, the synergistic effect of this dual-antibiotic hydrogel combined with PTT provides a creative strategy for eliminating drug-resistant bacteria in chronic infection wounds.202539760335
53980.8581A role of ygfZ in the Escherichia coli response to plumbagin challenge. Plumbagin is found in many herbal plants and inhibits the growth of various bacteria. Escherichia coli strains are relatively resistant to this drug. The mechanism of resistance is not clear. Previous findings showed that plumbagin treatment triggered up-regulation of many genes in E. coli including ahpC, mdaB, nfnB, nfo, sodA, yggX and ygfZ. By analyzing minimal inhibition concentration and inhibition zones of plumbagin in various gene-disruption mutants, ygfZ and sodA were found critical for the bacteria to resist plumbagin toxicity. We also found that the roles of YgfZ and SodA in detoxifying plumbagin are independent of each other. This is because of the fact that ectopically expressed SodA reduced the superoxide stress but not restore the resistance of bacteria when encountering plumbagin at the absence of ygfZ. On the other hand, an ectopically expressed YgfZ was unable to complement and failed to rescue the plumbagin resistance when sodA was perturbed. Furthermore, mutagenesis analysis showed that residue Cys228 within YgfZ fingerprint region was critical for the resistance of E. coli to plumbagin. By solvent extraction and HPLC analysis to follow the fate of the chemical, it was found that plumbagin vanished apparently from the culture of YgfZ-expressing E. coli. A less toxic form, methylated plumbagin, which may represent one of the YgfZ-dependent metabolites, was found in the culture supernatant of the wild type E. coli but not in the ΔygfZ mutant. Our results showed that the presence of ygfZ is not only critical for the E coli resistance to plumbagin but also facilitates the plumbagin degradation.201021059273
62090.8578Transcriptomic Responses and Survival Mechanisms of Staphylococci to the Antimicrobial Skin Lipid Sphingosine. Sphingosines are antimicrobial lipids that form part of the innate barrier to skin colonization by microbes. Sphingosine deficiencies can result in increased epithelial infections by bacteria including Staphylococcus aureus. Recent studies have focused on the potential use of sphingosine resistance or its potential mechanisms. We used RNA-Seq to identify the common d-sphingosine transcriptomic response of the transient skin colonizer S. aureus and the dominant skin coloniser S. epidermidis. A common d-sphingosine stimulon was identified that included downregulation of the SaeSR two-component system (TCS) regulon and upregulation of both the VraSR TCS and CtsR stress regulons. We show that the PstSCAB phosphate transporter, and VraSR offer intrinsic resistance to d-sphingosine. Further, we demonstrate increased sphingosine resistance in these staphylococci evolves readily through mutations in genes encoding the FarE-FarR efflux/regulator proteins. The ease of selecting mutants with resistance to sphingosine may impact upon staphylococcal colonization of skin where the lipid is present and have implications with topical therapeutic applications.202234902269
9734100.8578Combination 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
8472110.8576Genetic architecture of resistance to plant secondary metabolites in Photorhabdus entomopathogenic bacteria. BACKGROUND: Entomopathogenic nematodes of the genus Heterorhabditis establish a symbiotic association with Photorhabdus bacteria. Together, they colonize and rapidly kill insects, making them important biological control agents against agricultural pests. Improving their biocontrol traits by engineering resistance to plant secondary metabolites (benzoxazinoids) in Photorhabdus symbiotic bacteria through experimental evolution has been shown to increase their lethality towards benzoxazinoid-defended larvae of the western corn rootworm, a serious crop pest of maize, and it is therefore a promising approach to develop more efficient biocontrol agents to manage this pest. To enhance our understanding of the genetic bases of benzoxazinoid resistance in Photorhabdus bacteria, we conducted an experimental evolution experiment with a phylogenetically diverse collection of Photorhabdus strains from different geographic origins. We cultured 27 different strains in medium containing 6-methoxy-2-benzoxazolinone (MBOA), a highly active benzoxazinoid breakdown product, for 35 24 h-cycles to select for benzoxazinoid-resistant strains. Then, we carried out genome-wide sequence comparisons to uncover the genetic alterations associated with benzoxazinoid resistance. Lastly, we evaluated the resistance of the newly isolated resistant Photorhabdus strains to eight additional bioactive compounds, including 2-benzoxazolinone (BOA), nicotine, caffeine, 6-chloroacetyl-2-benzoxazolinone (CABOA), digitoxin, fenitrothion, ampicillin, and kanamycin. RESULTS: We found that benzoxazinoid resistance evolves rapidly in Photorhabdus in a strain-specific manner. Across the different Photorhabdus strains, a total of nineteen nonsynonymous point mutations, two stop codon gains, and one frameshift were associated with higher benzoxazinoid resistance. The different genetic alterations were polygenic and occurred in genes coding for the EnvZ/OmpR two-component regulatory system, the different subunits of the DNA-directed RNA polymerase, and the AcrABZ-TolC multidrug efflux pump. Apart from increasing MBOA resistance, the different mutations were also associated with cross-resistance to 2-benzoxazolinone (BOA), nicotine, caffeine, and 6-chloroacetyl-2-benzoxazolinone (CABOA) and with collateral sensitivity to fenitrothion, ampicillin, and kanamycin. Targeted mutagenesis will provide a deeper mechanistic understanding, including the relative contribution of the different mutation types. CONCLUSIONS: Our study reveals several genomic features that are associated with resistance to xenobiotics in this important group of biological control agents and enhances the availability of molecular tools to develop better biological control agents, which is essential for more sustainable and ecologically friendly agricultural practices.202541168779
8717120.8576Protective Effect of Pediococcus pentosaceus Li05 on Constipation via TGR5/TPH1/5-HT Activation. Pediococcus pentosaceus Li05, a strain of lactic acid bacteria isolated from the faeces of healthy volunteers, exhibited potential protective effects against various diseases. This study performed third-generation sequencing and detailed characterisation of its genome. The Li05 chromosome harboured conserved genes associated with acid resistance (atp), bile salt resistance (bsh), oxidative stress resistance (hsl, dltA, and et al.), and adhesion (nrd, gap, and et al.), whereas the plasmid did not contain antibiotic resistance or virulence genes. Following intervention with Li05 in loperamide-induced constipated mice, constipation symptoms improved. Meanwhile, alterations in gut microbiota, increased BSH activity in faeces, and modifications to the faecal bile acid profile were observed. Additionally, expression levels of TGR5 and TPH1 in the colon of the mice increased, leading to elevated 5-HT levels. When the TGR5 gene was knocked out or the TPH1 inhibitor LX1606 was administered to suppress 5-HT synthesis in constipated mice, the beneficial effects of Li05 on gastrointestinal motility and mucus secretion were reversed. Culturing intestinal organoids demonstrated that increased bile acids such as DCA, Iso-LCA, and EALCA could enhance 5-HT levels through the TGR5/TPH1 axis. Therefore, we concluded that Li05 regulated bile acid metabolism, subsequently increasing 5-HT levels through the TGR5/TPH1 axis, thus alleviating constipation.202541159760
9008130.8575Dissolvable alginate hydrogel-based biofilm microreactors for antibiotic susceptibility assays. Biofilms are found in many infections in the forms of surface-adhering aggregates on medical devices, small clumps in tissues, or even in synovial fluid. Although antibiotic resistance genes are studied and monitored in the clinic, the structural and phenotypic changes that take place in biofilms can also lead to significant changes in how bacteria respond to antibiotics. Therefore, it is important to better understand the relationship between biofilm phenotypes and resistance and develop approaches that are compatible with clinical testing. Current methods for studying antimicrobial susceptibility are mostly planktonic or planar biofilm reactors. In this work, we develop a new type of biofilm reactor-three-dimensional (3D) microreactors-to recreate biofilms in a microenvironment that better mimics those in vivo where bacteria tend to form surface-independent biofilms in living tissues. The microreactors are formed on microplates, treated with antibiotics of 1000 times of the corresponding minimal inhibitory concentrations (1000 × MIC), and monitored spectroscopically with a microplate reader in a high-throughput manner. The hydrogels are dissolvable on demand without the need for manual scraping, thus enabling measurements of phenotypic changes. Bacteria inside the biofilm microreactors are found to survive exposure to 1000 × MIC of antibiotics, and subsequent comparison with plating results reveals no antibiotic resistance-associated phenotypes. The presented microreactor offers an attractive platform to study the tolerance and antibiotic resistance of surface-independent biofilms such as those found in tissues.202336691521
780140.8573Gausemycin A-Resistant Staphylococcus aureus Demonstrates Affected Cell Membrane and Cell Wall Homeostasis. Antibiotic resistance is a significant and pressing issue in the medical field, as numerous strains of infectious bacteria have become resistant to commonly prescribed antibiotics. Staphylococcus aureus is a bacterium that poses a grave threat, as it is responsible for a large number of nosocomial infections and has high mortality rates worldwide. Gausemycin A is a new lipoglycopeptide antibiotic that has considerable efficacy against multidrug-resistant S. aureus strains. Although the cellular targets of gausemycin A have been previously identified, detailing the molecular processes of action is still needed. We performed gene expression analysis to identify molecular mechanisms that may be involved in bacterial resistance to gausemycin A. In the present study, we observed that gausemycin A-resistant S. aureus in the late-exponential phase showed an increased expression of genes involved in cell wall turnover (sceD), membrane charge (dltA), phospholipid metabolism (pgsA), the two-component stress-response system (vraS), and the Clp proteolytic system (clpX). The increased expression of these genes implies that changes in the cell wall and cell membrane are essential for the bacterial resistance to gausemycin A. In the stationary phase, we observed a decrease in the expression of genes involved in the phospholipid metabolism (mprF) and Clp proteolytic system (clpX).202337317304
8176150.8571Overcoming Multidrug Resistance in Bacteria Through Antibiotics Delivery in Surface-Engineered Nano-Cargos: Recent Developments for Future Nano-Antibiotics. In the recent few decades, the increase in multidrug-resistant (MDR) bacteria has reached an alarming rate and caused serious health problems. The incidence of infections due to MDR bacteria has been accompanied by morbidity and mortality; therefore, tackling bacterial resistance has become an urgent and unmet challenge to be properly addressed. The field of nanomedicine has the potential to design and develop efficient antimicrobials for MDR bacteria using its innovative and alternative approaches. The uniquely constructed nano-sized antimicrobials have a predominance over traditional antibiotics because their small size helps them in better interaction with bacterial cells. Moreover, surface engineering of nanocarriers offers significant advantages of targeting and modulating various resistance mechanisms, thus owe superior qualities for overcoming bacterial resistance. This review covers different mechanisms of antibiotic resistance, application of nanocarrier systems in drug delivery, functionalization of nanocarriers, application of functionalized nanocarriers for overcoming bacterial resistance, possible limitations of nanocarrier-based approach for antibacterial delivery, and future of surface-functionalized antimicrobial delivery systems.202134307323
8161160.8570Integrative strategies against multidrug-resistant bacteria: Synthesizing novel antimicrobial frontiers for global health. Concerningly, multidrug-resistant bacteria have emerged as a prime worldwide trouble, obstructing the treatment of infectious diseases and causing doubts about the therapeutic accidentalness of presently existing drugs. Novel antimicrobial interventions deserve development as conventional antibiotics are incapable of keeping pace with bacteria evolution. Various promising approaches to combat MDR infections are discussed in this review. Antimicrobial peptides are examined for their broad-spectrum efficacy and reduced ability to develop resistance, while phage therapy may be used under extreme situations when antibiotics fail. In addition, the possibility of CRISPR-Cas systems for specifically targeting and eradicating resistance genes from bacterial populations will be explored. Nanotechnology has opened up the route to improve the delivery system of the drug itself, increasing the efficacy and specificity of antimicrobial action while protecting its host. Discovering potential antimicrobial agents is an exciting prospect through developments in synthetic biology and the rediscovery of natural product-based medicines. Moreover, host-directed therapies are now becoming popular as an adjunct to the main strategies of therapeutics without specifically targeting pathogens. Although these developments appear impressive, questions about production scaling, regulatory approvals, safety, and efficacy for clinical employment still loom large. Thus, tackling the MDR burden requires a multi-pronged plan, integrating newer treatment modalities with existing antibiotic regimens, enforcing robust stewardship initiatives, and effecting policy changes at the global level. The international health community can gird itself against the growing menace of antibiotic resistance if collaboration between interdisciplinary bodies and sustained research endeavours is encouraged. In this study, we evaluate the synergistic potential of combining various medicines in addition to summarizing recent advancements. To rethink antimicrobial stewardship in the future, we provide a multi-tiered paradigm that combines pathogen-focused and host-directed strategies.202540914328
9031170.8568EmrR-Dependent Upregulation of the Efflux Pump EmrCAB Contributes to Antibiotic Resistance in Chromobacterium violaceum. Chromobacterium violaceum is an environmental Gram-negative bacterium that causes infections in humans. Treatment of C. violaceum infections is difficult and little is known about the mechanisms of antibiotic resistance in this bacterium. In this work, we identified mutations in the MarR family transcription factor EmrR and in the protein GyrA as key determinants of quinolone resistance in C. violaceum, and we defined EmrR as a repressor of the MFS-type efflux pump EmrCAB. Null deletion of emrR caused increased resistance to nalidixic acid, but not to other quinolones or antibiotics of different classes. Moreover, the ΔemrR mutant showed decreased production of the purple pigment violacein. Importantly, we isolated C. violaceum spontaneous nalidixic acid-resistant mutants with a point mutation in the DNA-binding domain of EmrR (R92H), with antibiotic resistance profile similar to that of the ΔemrR mutant. Other spontaneous mutants with high MIC values for nalidixic acid and increased resistance to fluoroquinolones presented point mutations in the gene gyrA. Using DNA microarray, Northern blot and EMSA assays, we demonstrated that EmrR represses directly a few dozen genes, including the emrCAB operon and other genes related to transport, oxidative stress and virulence. This EmrR repression on emrCAB was relieved by salicylate. Although mutation of the C. violaceum emrCAB operon had no effect in antibiotic susceptibility or violacein production, deletion of emrCAB in an emrR mutant background restored antibiotic susceptibility and violacein production in the ΔemrR mutant. Using a biosensor reporter strain, we demonstrated that the lack of pigment production in ΔemrR correlates with the accumulation of quorum-sensing molecules in the cell supernatant of this mutant strain. Therefore, our data revealed that overexpression of the efflux pump EmrCAB via mutation and/or derepression of EmrR confers quinolone resistance and alters quorum-sensing signaling in C. violaceum, and that point mutation in emrR can contribute to emergence of antibiotic resistance in bacteria.201830498484
9014180.8567Role 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
9024190.8565Tackling Virulence of Pseudomonas aeruginosa by the Natural Furanone Sotolon. The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.202134356792