Identification of an anti-virulence drug that reverses antibiotic resistance in multidrug resistant bacteria. - Related Documents




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883601.0000Identification of an anti-virulence drug that reverses antibiotic resistance in multidrug resistant bacteria. The persistent incidence of high levels of multidrug-resistant (MDR) bacteria seriously endangers global public health. In response to MDR-associated infections, new antibacterial drugs and strategies are particularly needed. Screening to evaluate a potential compound to reverse antibiotic resistance is a good strategy to alleviate this crisis. In this paper, using high-throughput screening methods, we identified that oxyclozanide potentiated tetracycline antibiotics act against MDR bacterial pathogens by promoting intracellular accumulation of tetracycline in resistant bacteria. Furthermore, mechanistic studies demonstrated that oxyclozanide could directly kill bacteria by disrupting bacterial membrane and inducing the overproduction of bacterial reactive oxygen species. Oxyclozanide effectively reduced the production of virulence proteins in S. aureus and neutralized the produced α-hemolysin, thereby effectively alleviating the inflammatory response caused by bacteria. Finally, oxyclozanide significantly reversed tetracycline resistance in animal infection assays. In summary, these results demonstrated the capacity of oxyclozanide as a novel antibiotic adjuvant, antibacterial and anti-virulence multifunctional compound to circumvent MDR bacteria and improve the therapeutic effect of persistent infections caused by MDR bacteria worldwide.202235797943
976510.9994Daunorubicin resensitizes Gram-negative superbugs to the last-line antibiotics and prevents the transmission of antibiotic resistance. Although meropenem, colistin, and tigecycline are recognized as the last-line antibiotics for multidrug-resistant Gram-negative bacteria (MDR-GN), the emergence of mobile resistance genes such as bla(NDM), mcr, and tet(X) severely compromises their clinical effectiveness. Developing novel antibiotic adjuvants to restore the effectiveness of existing antibiotics provides a feasible approach to address this issue. Herein, we discover that a Food and Drug Administration (FDA)-approved drug daunorubicin (DNR) drastically potentiates the activity of last-resort antibiotics against MDR-GN pathogens and biofilm-producing bacteria. Furthermore, DNR effectively inhibits the evolution and spread of colistin and tigecycline resistance. Mechanistically, DNR and colistin combination exacerbates membrane disruption, induces DNA damage and the massive production of reactive oxygen species (ROS), ultimately leading to bacterial cell death. Importantly, DNR restores the effectiveness of colistin in Galleria mellonella and murine models of infection. Collectively, our findings provide a potential drug combination strategy for treating severe infections elicited by Gram-negative superbugs.202337235051
897820.9994Revealing the antibacterial power of hydrogen-releasing PdH nanohydride against drug resistant Staphylococcus aureus: an in-depth mechanism study. Currently, multidrug resistant (MDR) bacterial infections are a great threat to public health, and the development of novel strategies for high efficiency combatting of MDR bacteria is in urgent demand. Hydrogen (H(2)) is a small gas with a high reducing ability, and plenty of recent studies have demonstrated its therapeutic effect on many diseases. However, the antibacterial effectiveness and mechanism of H(2) against MDR bacteria are still unknown. In the present work, using PdH nanohydride with a temperature responsive H(2)-releasing property as the H(2) source, we demonstrated that H(2) was not only able to inhibit the growth of normal Staphylococcus aureus (S. aureus), but could also effectively eliminate single drug resistant S. aureus (CRSA) and multidrug resistant S. aureus (MRSA), as well as the biofilms formed by those bacteria. Moreover, an in-depth mechanism regarding the anti-antibiotic-resistance activity of H(2) was elucidated by us, in which H(2) exerted its antibacterial effect by firstly causing severe membrane damage, followed by boosting generation of intracellular ROS, which subsequently triggered DNA damage and finally led to bacterial death. The proposed mechanism was further verified by genomic analysis, where a cluster of genes related to bacterial membrane integrity, biofilm formation, metabolism and DNA functions was significantly perturbed by the released H(2). In particular, H(2) boosted intracellular ROS generation by destroying the redox homeostasis of bacterial metabolism. More importantly, we revealed that H(2) was able to alleviate the antibiotic resistance of CRSA and MRSA by significantly down-regulating the expression of many drug-resistant genes, e.g. the norG gene of CRSA, and fmtA, gpsB, sarA and marR genes of MRSA, as well as reducing the minimal inhibitory concentration (MIC) of ciprofloxacin/ampicillin against CRSA/MRSA. The findings in our work suggested that H(2) therapy is a promising tool for combating antibiotic-resistant bacteria.202336655922
896230.9994A Dietary Source of High Level of Fluoroquinolone Tolerance in mcr-Carrying Gram-Negative Bacteria. The emergence of antibiotic tolerance, characterized by the prolonged survival of bacteria following antibiotic exposure, in natural bacterial populations, especially in pathogens carrying antibiotic resistance genes, has been an increasing threat to public health. However, the major causes contributing to the formation of antibiotic tolerance and underlying molecular mechanisms are yet poorly understood. Herein, we show that potassium sorbate (PS), a widely used food additive, triggers a high level of fluoroquinolone tolerance in bacteria carrying mobile colistin resistance gene mcr. Mechanistic studies demonstrate that PS treatment results in the accumulation of intracellular fumarate, which activates bacterial two-component system and decreases the expression level of outer membrane protein OmpF, thereby reducing the uptake of ciprofloxacin. In addition, the supplementation of PS inhibits aerobic respiration, reduces reactive oxygen species production and alleviates DNA damage caused by bactericidal antibiotics. Furthermore, we demonstrate that succinate, an intermediate product of the tricarboxylic acid cycle, overcomes PS-mediated ciprofloxacin tolerance. In multiple animal models, ciprofloxacin treatment displays failure outcomes in PS preadministrated animals, including comparable survival and bacterial loads with the vehicle group. Taken together, our works offer novel mechanistic insights into the development of antibiotic tolerance and uncover potential risks associated with PS use.202337808177
980440.9994Antimicrobial Peptides as an Alternative for the Eradication of Bacterial Biofilms of Multi-Drug Resistant Bacteria. Bacterial resistance is an emergency public health problem worldwide, compounded by the ability of bacteria to form biofilms, mainly in seriously ill hospitalized patients. The World Health Organization has published a list of priority bacteria that should be studied and, in turn, has encouraged the development of new drugs. Herein, we explain the importance of studying new molecules such as antimicrobial peptides (AMPs) with potential against multi-drug resistant (MDR) and extensively drug-resistant (XDR) bacteria and focus on the inhibition of biofilm formation. This review describes the main causes of antimicrobial resistance and biofilm formation, as well as the main and potential AMP applications against these bacteria. Our results suggest that the new biomacromolecules to be discovered and studied should focus on this group of dangerous and highly infectious bacteria. Alternative molecules such as AMPs could contribute to eradicating biofilm proliferation by MDR/XDR bacteria; this is a challenging undertaking with promising prospects.202235336016
897750.9994Novel Lignin-Capped Silver Nanoparticles against Multidrug-Resistant Bacteria. The emergence of bacteria resistant to antibiotics and the resulting infections are increasingly becoming a public health issue. Multidrug-resistant (MDR) bacteria are responsible for infections leading to increased morbidity and mortality in hospitals, prolonged time of hospitalization, and additional burden to financial costs. Therefore, there is an urgent need for novel antibacterial agents that will both treat MDR infections and outsmart the bacterial evolutionary mechanisms, preventing further resistance development. In this study, a green synthesis employing nontoxic lignin as both reducing and capping agents was adopted to formulate stable and biocompatible silver-lignin nanoparticles (NPs) exhibiting antibacterial activity. The resulting silver-lignin NPs were approximately 20 nm in diameter and did not agglomerate after one year of storage at 4 °C. They were able to inhibit the growth of a panel of MDR clinical isolates, including Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, at concentrations that did not affect the viability of a monocyte-derived THP-1 human cell line. Furthermore, the exposure of silver-lignin NPs to the THP-1 cells led to a significant increase in the secretion of the anti-inflammatory cytokine IL-10, demonstrating the potential of these particles to act as an antimicrobial and anti-inflammatory agent simultaneously. P. aeruginosa genes linked with efflux, heavy metal resistance, capsular biosynthesis, and quorum sensing were investigated for changes in gene expression upon sublethal exposure to the silver-lignin NPs. Genes encoding for membrane proteins with an efflux function were upregulated. However, all other genes were membrane proteins that did not efflux metals and were downregulated.202133945683
884860.9994Harnessing the effect of iron deprivation to attenuate the growth of opportunistic pathogen Acinetobacter baumannii. Acinetobacter baumannii is an opportunistic pathogen having high infectivity among immunocompromised patients. The bacteria are resistant to major first-line antibiotics and have become a serious concern in the aspect of nosocomial and community-acquired infections. To overcome this dire situation, the necessity of introducing new approaches is undeniable, which can bypass the need for conventional antibiotic therapy. In this article, we have pinpointed the importance of iron in A. baumannii. Iron is an essential micronutrient in all bacteria. Loss of iron acquisition leads to membrane destabilization, and change in the expression of iron-transporting or -metabolizing genes causes death of the bacteria. Iron scavenging was primarily mediated by different chelators, and β-thujaplicin showed the best antibacterial efficacy with respect to time killing assay and CFU analysis. When iron (Fe(2+)) was supplemented after initial deficiency, the growth of the bacteria was seen to be restored. Iron deprivation also disintegrates the biofilm matrix, a major cause of bacterial resistance against different types of antibiotics. Moreover, iron scavenging promotes inhibition of biofilm sessile persister cells, the root cause of recalcitrant and chronic infection. As a part of antimicrobial therapy, β-thujaplicin was treated alongside colistin and chloramphenicol at an amount significantly lower than its MIC value. Our results indicated that β-thujaplicin nicely complemented those antibiotics to potentiate their antimicrobial action. In a nutshell, iron chelating agents are potential alternative therapeutics that can be used alongside different antibiotics to circumvent the resistance of different nosocomial pathogens.202540202344
885070.9994Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides. Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.201829795541
976780.9994Metallo-β-lactamase NDM-1 serves as a universal vaccine candidate for combatting antimicrobial resistance. The rapid emergence and spread of antimicrobial resistance have become critical global health issues, leading to significant morbidity and mortality worldwide. With the increase in resistance to multiple drugs, especially frontline clinical antibiotics, there is an urgent need for novel and effective alternative strategies. Herein, we developed a vaccine targeting the antimicrobial resistance enzyme NDM-1, which was first identified in Klebsiella pneumoniae and has quickly spread to other gram-negative bacteria. Our results demonstrate that NDM-1 primarily triggers a humoral immune response and effectively protects mice from lethal Klebsiella pneumoniae infection, as evidenced by increased survival rates, reduced bacterial loads, and decreased lung inflammation in mice. The specific antibodies generated were able to inhibit the enzymatic activity of NDM-1, bacterial growth, and exhibit opsonophagocytic activity against Klebsiella pneumoniae in vitro. Both active and passive immunization with NDM-1 showed an additive effect when combined with meropenem therapy. Furthermore, NDM-1 immunization induced cross-reactivity with NDM-1 variants, potentially providing broad protection against bacteria carrying different NDM genes. Additionally, heptamerization of NDM-1 improved its immunogenicity and protective efficacy in mice. These results highlight the potential of vaccine development based on antibiotic resistance candidates for broadly combatting antimicrobial resistance.202540505900
954690.9993Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria. Bacterial resistance has intensified in recent years due to the uncontrolled use of conventional drugs, and new bacterial strains with multiple resistance have been reported. This problem may be solved by using antimicrobial peptides (AMPs), which fulfill their bactericidal activity without developing much bacterial resistance. The rapid interaction between AMPs and the bacterial cell membrane means that the bacteria cannot easily develop resistance mechanisms. In addition, various drugs for clinical use have lost their effect as a conventional treatment; however, the synergistic effect of AMPs with these drugs would help to reactivate and enhance antimicrobial activity. Their efficiency against multi-resistant and extensively resistant bacteria has positioned them as promising molecules to replace or improve conventional drugs. In this review, we examined the importance of antimicrobial peptides and their successful activity against critical and high-priority bacteria published in the WHO list.202134064302
9540100.9993Coping with antibiotic resistance: combining nanoparticles with antibiotics and other antimicrobial agents. The worldwide escalation of bacterial resistance to conventional medical antibiotics is a serious concern for modern medicine. High prevalence of multidrug-resistant bacteria among bacteria-based infections decreases effectiveness of current treatments and causes thousands of deaths. New improvements in present methods and novel strategies are urgently needed to cope with this problem. Owing to their antibacterial activities, metallic nanoparticles represent an effective solution for overcoming bacterial resistance. However, metallic nanoparticles are toxic, which causes restrictions in their use. Recent studies have shown that combining nanoparticles with antibiotics not only reduces the toxicity of both agents towards human cells by decreasing the requirement for high dosages but also enhances their bactericidal properties. Combining antibiotics with nanoparticles also restores their ability to destroy bacteria that have acquired resistance to them. Furthermore, nanoparticles tagged with antibiotics have been shown to increase the concentration of antibiotics at the site of bacterium-antibiotic interaction, and to facilitate binding of antibiotics to bacteria. Likewise, combining nanoparticles with antimicrobial peptides and essential oils generates genuine synergy against bacterial resistance. In this article, we aim to summarize recent studies on interactions between nanoparticles and antibiotics, as well as other antibacterial agents to formulate new prospects for future studies. Based on the promising data that demonstrated the synergistic effects of antimicrobial agents with nanoparticles, we believe that this combination is a potential candidate for more research into treatments for antibiotic-resistant bacteria.201122029522
9751110.9993Antibiotics-free compounds for managing carbapenem-resistant bacteria; a narrative review. Carbapenem-resistant (CR) Gram-negative bacteria have become a significant public health problem in the last decade. In recent years, the prevalence of CR bacteria has increased. The resistance to carbapenems could result from different mechanisms such as loss of porin, penicillin-binding protein alteration, carbapenemase, efflux pump, and biofilm community. Additionally, genetic variations like insertion, deletion, mutation, and post-transcriptional modification of corresponding coding genes could decrease the susceptibility of bacteria to carbapenems. In this regard, scientists are looking for new approaches to inhibit CR bacteria. Using bacteriophages, natural products, nanoparticles, disulfiram, N-acetylcysteine, and antimicrobial peptides showed promising inhibitory effects against CR bacteria. Additionally, the mentioned compounds could destroy the biofilm community of CR bacteria. Using them in combination with conventional antibiotics increases the efficacy of antibiotics, decreases their dosage and toxicity, and resensitizes CR bacteria to antibiotics. Therefore, in the present review article, we have discussed different aspects of non-antibiotic approaches for managing and inhibiting the CR bacteria and various methods and procedures used as an alternative for carbapenems against these bacteria.202439355778
4769120.9993Human breast milk isolated lactic acid bacteria: antimicrobial and immunomodulatory activity on the Galleria mellonella burn wound model. INTRODUCTION: Managing burn injuries is a challenge in healthcare. Due to the alarming increase in antibiotic resistance, new prophylactic and therapeutic strategies are being sought. This study aimed to evaluate the potential of live Lactic Acid Bacteria for managing burn infections, using Galleria mellonella larvae as an alternative preclinical animal model and comparing the outcomes with a common antibiotic. METHODS: The antimicrobial activity of LAB isolated from human breast milk was assessed in vitro against Pseudomonas aeruginosa ATCC 27853. Additionally, the immunomodulatory effects of LAB were evaluated in vivo using the G. mellonella burn wound infection model. RESULTS AND DISCUSSION: In vitro results demonstrated the antimicrobial activity of Lactic Acid Bacteria against P. aeruginosa. In vivo results show that their prophylactic treatment improves, statistically significant, larval survival and modulates the expression of immunity-related genes, Gallerimycin and Relish/NF-κB, strain-dependently. These findings lay the foundation and suggest a promising alternative for burn wound prevention and management, reducing the risk of antibiotic resistance, enhancing immune modulation, and validating the potential G. mellonella as a skin burn wound model.202439310784
4699130.9993Exposure to DDAB disinfectants promotes antimicrobial resistance to antibiotics and collateral-sensitivity to polymyxins in Salmonella enterica. SALMONELLA: as an important food-borne zoonotic pathogen, is found in soil and processing environment by human or animal feces, causing serious public health problems. Quaternary ammonium compounds (QACs) disinfectants are widely used in hospitals, livestock farms and food processing sites because of their low toxicity and broad-spectrum disinfection. However, sub-lethal levels of QACs disinfectants can induce bacteria to develop tolerance to disinfectants and cross-resistance to other antimicrobial agents. The acquired resistance will undoubtedly pose a threat to the prevention of antimicrobial resistance. In this study, Salmonella enterica SE211 was induced by the sub-inhibitory concentration and sub-lethal concentration of dodecyl dimethyl ammonium bromide (DDAB) in vitro. Following exposure to DDAB, the strains showed increased resistance to DDAB, doxycycline, amphenicols and fluoroquinolones, and increased sensitivity to colistin drugs. Phenotypic experiments showed that the induced strains exhibited changes in efflux pump activity, biofilm formation ability, motility and membrane characterization. Next-generation sequencing revealed mutations in induced strains involved in LPS-related genes (msbA, lptDE) and cationic antimicrobial peptide (CAMP) resistance-related genes (phoQ, pmrD). Transcriptome sequencing (RNA-seq) analysis revealed up-regulation of efflux pump genes and down-regulation of CAMP resistance, LPS and peptidoglycan related genes. Our study provided a theoretical basis for the potential consequences of disinfection failures and environmental residues of QACs disinfectants on the evolution of antibiotic resistance in salmonella. Furthermore, the induction of colistin sensitivity in salmonella by DDBA resulted in the emergence of collateral sensitivity, which offered a new strategy for drug combination applications to prevent the rise of colistin-resistant superbugs.202540021029
8975140.9993Targeting bacterial biofilm-related genes with nanoparticle-based strategies. Persistent infection caused by biofilm is an urgent in medicine that should be tackled by new alternative strategies. Low efficiency of classical treatments and antibiotic resistance are the main concerns of the persistent infection due to biofilm formation which increases the risk of morbidity and mortality. The gene expression patterns in biofilm cells differed from those in planktonic cells. One of the promising approaches against biofilms is nanoparticle (NP)-based therapy in which NPs with multiple mechanisms hinder the resistance of bacterial cells in planktonic or biofilm forms. For instance, NPs such as silver (Ag), zinc oxide (ZnO), titanium dioxide (TiO(2)), copper oxide (Cu), and iron oxide (Fe(3)O(4)) through the different strategies interfere with gene expression of bacteria associated with biofilm. The NPs can penetrate into the biofilm structure and affect the expression of efflux pump, quorum-sensing, and adhesion-related genes, which lead to inhibit the biofilm formation or development. Therefore, understanding and targeting of the genes and molecular basis of bacterial biofilm by NPs point to therapeutic targets that make possible control of biofilm infections. In parallel, the possible impact of NPs on the environment and their cytotoxicity should be avoided through controlled exposure and safety assessments. This study focuses on the biofilm-related genes that are potential targets for the inhibition of bacterial biofilms with highly effective NPs, especially metal or metal oxide NPs.202438841057
9538150.9993The Mechanism of Bacterial Resistance and Potential Bacteriostatic Strategies. Bacterial drug resistance is rapidly developing as one of the greatest threats to human health. Bacteria will adopt corresponding strategies to crack the inhibitory effect of antibiotics according to the antibacterial mechanism of antibiotics, involving the mutation of drug target, secreting hydrolase, and discharging antibiotics out of cells through an efflux pump, etc. In recent years, bacteria are found to constantly evolve new resistance mechanisms to antibiotics, including target protective protein, changes in cell morphology, and so on, endowing them with multiple defense systems against antibiotics, leading to the emergence of multi-drug resistant (MDR) bacteria and the unavailability of drugs in clinics. Correspondingly, researchers attempt to uncover the mystery of bacterial resistance to develop more convenient and effective antibacterial strategies. Although traditional antibiotics still play a significant role in the treatment of diseases caused by sensitive pathogenic bacteria, they gradually lose efficacy in the MDR bacteria. Therefore, highly effective antibacterial compounds, such as phage therapy and CRISPER-Cas precision therapy, are gaining an increasing amount of attention, and are considered to be the treatments with the moist potential with regard to resistance against MDR in the future. In this review, nine identified drug resistance mechanisms are summarized, which enhance the retention rate of bacteria under the action of antibiotics and promote the distribution of drug-resistant bacteria (DRB) in the population. Afterwards, three kinds of potential antibacterial methods are introduced, in which new antibacterial compounds exhibit broad application prospects with different action mechanisms, the phage therapy has been successfully applied to infectious diseases caused by super bacteria, and the CRISPER-Cas precision therapy as a new technology can edit drug-resistant genes in pathogenic bacteria at the gene level, with high accuracy and flexibility. These antibacterial methods will provide more options for clinical treatment, and will greatly alleviate the current drug-resistant crisis.202236139994
8851160.9993Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy. The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene's sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities.201627631336
6285170.9993Triton X-100 counteracts antibiotic resistance of Enterococcus faecalis: An in vitro study. OBJECTIVES: The high prevalence of antibiotic-resistant bacteria poses a threat to the global public health. The appropriate use of adjuvants to restore the antimicrobial activity of antibiotics against resistant bacteria could be an effective strategy for combating antibiotic resistance. In this study, we investigated the counteraction of Triton X-100 (TX-100) and the mechanisms underlying the antibiotic resistance of Enterococcus faecalis (E. faecalis). METHODS: Standard, wild-type (WT), and induced antibiotic-resistant E. faecalis strains were used in this study. In vitro antibacterial experiments were conducted to evaluate the antimicrobial activities of gentamicin sulfate and ciprofloxacin hydrochloride in the presence and absence of 0.02 % TX-100 against both planktonic and biofilm bacteria. Transcriptomic and untargeted metabolomic analyses were performed to explore the molecular mechanisms of TX-100 as an antibiotic adjuvant. Additionally, membrane permeability, membrane potential, glycolysis-related enzyme activity, intracellular adenosine triphosphate (ATP), and expression levels of virulence genes were assessed. The biocompatibility of different drug combinations was also evaluated. RESULTS: A substantially low TX-100 concentration improved the antimicrobial effects of gentamicin sulfate or ciprofloxacin hydrochloride against antibiotic-resistant E. faecalis. Mechanistic studies demonstrated that TX-100 increased cell membrane permeability and dissipated membrane potential. Moreover, antibiotic resistance and pathogenicity of E. faecalis were attenuated by TX-100 via downregulation of the ABC transporter, phosphotransferase system (PTS), and ATP supply. CONCLUSIONS: TX-100 enhanced the antimicrobial activity of gentamicin sulfate and ciprofloxacin hydrochloride at a low concentration by improving antibiotic susceptibility and attenuating antibiotic resistance and pathogenicity of E. faecalis. CLINICAL SIGNIFICANCE: These findings provide a theoretical basis for developing new root canal disinfectants that can reduce antibiotic resistance.202438729285
9770180.9993Exogenous adenosine counteracts tigecycline resistance in tet(X3)-harboring Escherichia coli. The rapid spread of antibiotic resistance poses a global health crisis. Tigecycline is a last-resort antibiotic, but the recent emergence of the plasmid-borne tet(X3) gene conferring high-level tigecycline resistance is deeply concerning. Here, we report a metabolomics-guided approach to overcome tet(X3)-mediated resistance. Using untargeted metabolomics, we identified adenosine as a key metabolic biomarker associated with tet(X3) expression. Remarkably, supplementation with exogenous adenosine was able to restore tigecycline susceptibility in tet(X3)-positive Escherichia coli both in vitro and in vivo. Our mechanistic investigations reveal that adenosine enhances the bactericidal effects of tigecycline by inducing oxidative stress, DNA/RNA damage, and cell membrane disruption in resistant bacteria. This study establishes a powerful metabolomics-driven strategy to potentiate antibiotic efficacy against drug-resistant pathogens. The adenosine-based adjuvant therapy represents a promising approach to combat the global crisis of antibiotic resistance.IMPORTANCEThe emergence and widespread dissemination of the high-level tigecycline resistance gene tet(X3) have posed a significant challenge to the efficacy of tigecycline, which serves as the "last line of defense" against antimicrobial-resistant bacteria. Although tigecycline has not been approved for veterinary clinical use, constant detection of tet(X3) genes and new subtypes in livestock farming environments poses a substantial threat to public health safety. While developing novel antibiotics is an effective approach to eradicate resistance genes/bacteria, it entails considerable costs and a lengthy timeframe. This study discovered that exogenous adenosine can effectively restore the sensitivity of tet(X3)-positive Escherichia coli to tigecycline through metabolic reprogramming based on a non-targeted metabolomics strategy. The findings are highly significant for exploring comprehensive mechanisms underlying bacterial multidrug resistance, utilizing metabolic reprogramming strategies to curb the spread of novel resistant genes, and treating clinical infections caused by tet(X3)-positive bacteria.202540622216
9544190.9993Nano-Strategies to Fight Multidrug Resistant Bacteria-"A Battle of the Titans". Infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. Therefore, the antibiotic resistance crisis is one of the most pressing issues in global public health. Associated with the rise in antibiotic resistance is the lack of new antimicrobials. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds as well as to develop novel delivery and targeting strategies. Bacteria have developed many ways by which they become resistant to antimicrobials. Among those are enzyme inactivation, decreased cell permeability, target protection, target overproduction, altered target site/enzyme, increased efflux due to over-expression of efflux pumps, among others. Other more complex phenotypes, such as biofilm formation and quorum sensing do not appear as a result of the exposure of bacteria to antibiotics although, it is known that biofilm formation can be induced by antibiotics. These phenotypes are related to tolerance to antibiotics in bacteria. Different strategies, such as the use of nanostructured materials, are being developed to overcome these and other types of resistance. Nanostructured materials can be used to convey antimicrobials, to assist in the delivery of novel drugs or ultimately, possess antimicrobial activity by themselves. Additionally, nanoparticles (e.g., metallic, organic, carbon nanotubes, etc.) may circumvent drug resistance mechanisms in bacteria and, associated with their antimicrobial potential, inhibit biofilm formation or other important processes. Other strategies, including the combined use of plant-based antimicrobials and nanoparticles to overcome toxicity issues, are also being investigated. Coupling nanoparticles and natural-based antimicrobials (or other repurposed compounds) to inhibit the activity of bacterial efflux pumps; formation of biofilms; interference of quorum sensing; and possibly plasmid curing, are just some of the strategies to combat multidrug resistant bacteria. However, the use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this. In this review, we will summarize the current research on nanoparticles and other nanomaterials and how these are or can be applied in the future to fight multidrug resistant bacteria.201830013539