Dataset Information

Exposure to One Antibiotic Leads to Acquisition of Resistance to Another Antibiotic via Quorum Sensing Mechanisms.

ABSTRACT: The vancomycin-resistant Enterococci (VRE) have progressively become a severe medical problem. Although clinics have started to reduce vancomycin prescription, vancomycin resistance has not been contained. We found that the transfer of vancomycin resistance in Enterococcus faecalis increased more than 30-fold upon treatment by streptomycin. Notably, treatment with an antibiotic caused the bacteria to become resistant to another. The response was even stronger in the well-studied plasmid pCF10 and the number of transconjugants increased about 100,000-fold. We tested four different antibiotics, and all of them induced conjugal response. Through a mathematical model based on gene regulation, we found a plausible explanation. Via quorum sensing, the change of the cell density triggers the conjugation. Moreover, we searched for generality and found a similar strategy in Bacillus subtilis. The outcome of the present study suggests that even common antibiotics must not be overused.

SUBMITTER: Shu CC

PROVIDER: S-EPMC7855173 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exposure to One Antibiotic Leads to Acquisition of Resistance to Another Antibiotic <i>via</i> Quorum Sensing Mechanisms.

Shu Che-Chi CC Chen Wan-Ci WC Chang Yao-Duo YD Chen Jyy-Ning JN Liu Feng-You FY Huang Yu-Shan YS You Chao-Xuan CX Wu En Hsuan EH

Frontiers in microbiology 20210120

The vancomycin-resistant Enterococci (VRE) have progressively become a severe medical problem. Although clinics have started to reduce vancomycin prescription, vancomycin resistance has not been contained. We found that the transfer of vancomycin resistance in <i>Enterococcus faecalis</i> increased more than 30-fold upon treatment by streptomycin. Notably, treatment with an antibiotic caused the bacteria to become resistant to another. The response was even stronger in the well-studied plasmid p ...[more]

PMID: 33552007

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Project description:Quorum sensing (QS) is a cell-density-dependent, intercellular communication system mediated by small diffusible signaling molecules. QS regulates a range of bacterial behaviors, including biofilm formation, virulence, drug resistance mechanisms, and antibiotic tolerance. Enzymes capable of degrading signaling molecules can interfere in QS-a process termed as quorum quenching (QQ). Remarkably, previous work reported some cases where enzymatic interference in QS was synergistic to antibiotics against Pseudomonas aeruginosa. The premise of combination therapy is attractive to fight against multidrug-resistant bacteria, yet comprehensive studies are lacking. Here, we evaluate the effects of QS signal disruption on the antibiotic resistance profile of P. aeruginosa by testing 222 antibiotics and antibacterial compounds from 15 different classes. We found compelling evidence that QS signal disruption does indeed affect antibiotic resistance (40% of all tested compounds; 89/222), albeit not always synergistically (not synergistic for 19% of compounds; 43/222). For some tested antibiotics, such as sulfathiazole and trimethoprim, we were able to relate the changes in resistance caused by QS signal disruption to the modulation of the expression of key genes of the folate biosynthetic pathway. Moreover, using a P. aeruginosa-based Caenorhabditis elegans killing model, we confirmed that enzymatic QQ modulates the effects of antibiotics on P. aeruginosa's pathogenicity in vivo. Altogether, these results show that signal disruption has profound and complex effects on the antibiotic resistance profile of P. aeruginosa. This work suggests that combination therapy including QQ and antibiotics should be discussed not globally but, rather, in case-by-case studies. IMPORTANCE Quorum sensing (QS) is a cell-density-dependent communication system used by a wide range of bacteria to coordinate behaviors. Strategies pertaining to the interference in QS are appealing approaches to control microbial behaviors that depend on QS, including virulence and biofilms. Interference in QS was previously reported to be synergistic with antibiotics, yet no systematic assessment exists. Here, we evaluate the potential of combination treatments using the model opportunistic human pathogen Pseudomonas aeruginosa PA14. In this model, collected data demonstrate that QS largely modulates the antibiotic resistance profile of PA14 (for more than 40% of the tested drugs). However, the outcome of combination treatments is synergistic for only 19% of them. This research demonstrates the complex relationship between QS and antibiotic resistance and suggests that combination therapy including QS inhibitors and antibiotics should be discussed not globally but, rather, in case-by-case studies.

Project description:UnlabelledStaphylococcus aureus is a human commensal that at times turns into a serious bacterial pathogen causing life-threatening infections. For the delicate control of virulence, S. aureus employs the agr quorum-sensing system that, via the intracellular effector molecule RNAIII, regulates virulence gene expression. We demonstrate that the presence of the agr locus imposes a fitness cost on S. aureus that is mediated by the expression of RNAIII. Further, we show that exposure to sublethal levels of the antibiotics ciprofloxacin, mupirocin, and rifampin, each targeting separate cellular functions, markedly increases the agr-mediated fitness cost by inducing the expression of RNAIII. Thus, the extensive use of antibiotics in hospitals may explain why agr-negative variants are frequently isolated from hospital-acquired S. aureus infections but rarely found among community-acquired S. aureus strains. Importantly, agr deficiency correlates with increased duration of and mortality due to bacteremia during antibiotic treatment and with a higher frequency of glycopeptide resistance than in agr-carrying strains. Our results provide an explanation for the frequent isolation of agr-defective strains from hospital-acquired S. aureus infections and suggest that the adaptability of S. aureus to antibiotics involves the agr locus.ImportanceStaphylococcus aureus is the most frequently isolated pathogen in intensive care units and a common cause of nosocomial infections, resulting in a high degree of morbidity and mortality. Surprisingly, a large fraction (15 to 60%) of hospital-isolated S. aureus strains are agr defective and lack the main quorum-sensing-controlled virulence regulatory system. This is a problem, as agr-defective strains are associated with a mortality level in bacteremic infections and a probability of glycopeptide resistance greater than those of other strains. We show here that agr-negative strains have a fitness advantage over agr-positive strains in the presence of sublethal concentrations of some antibiotics and that the fitness defect of agr-positive cells is caused by antibiotic-mediated expression of the agr effector molecule RNAIII. These results offer an explanation of the frequent isolation of agr-defective S. aureus strains in hospitals and will influence how we treat S. aureus infections.

Dataset Information

Exposure to One Antibiotic Leads to Acquisition of Resistance to Another Antibiotic via Quorum Sensing Mechanisms.

Publications

Exposure to One Antibiotic Leads to Acquisition of Resistance to Another Antibiotic <i>via</i> Quorum Sensing Mechanisms.

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