scholarly journals Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1620
Author(s):  
Victor Markus ◽  
Karina Golberg ◽  
Kerem Teralı ◽  
Nazmi Ozer ◽  
Esti Kramarsky-Winter ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Conformational Changes ◽  
Mode Of Action ◽  
Pathogenic Bacteria ◽  
Molecular Targets ◽  
Resistant Bacteria ◽  
Public Healthcare ◽  
C 30

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.

scholarly journals The quorum sensing inhibitor furanone C-30 rapidly loses its tobramycin potentiating activity against Pseudomonas aeruginosa biofilms during experimental evolution

2021 ◽  
Author(s):  
Mona Bové ◽  
Xuerui Bao ◽  
Andrea Sass ◽  
Aurélie Crabbé ◽  
Tom Coenye
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Experimental Evolution ◽  
Aminoglycoside Antibiotic ◽  
Sequencing Analysis ◽  
Cystic Fibrosis Sputum ◽  
Quorum Sensing Inhibitors ◽  
C 30

The use of quorum sensing inhibitors (QSI) has been proposed as an alternative strategy to combat antibiotic resistance. QSI reduce the virulence of a pathogen without killing it and it is claimed that resistance to such compounds is less likely to develop although there is a lack of experimental data supporting this hypothesis. Additionally, such studies are often carried out in conditions that do not mimic the in vivo situation. In the present study, we evaluated whether a combination of the QSI furanone C-30 and the aminoglycoside antibiotic tobramycin is ‘evolution-proof’ when it is used to eradicate Pseudomonas aeruginosa biofilms grown in a synthetic cystic fibrosis sputum medium. We found that the biofilm eradicating activity of the tobramycin/furanone C-30 combination decreased already after 5 treatment cycles. The antimicrobial susceptibility of P. aeruginosa to tobramycin decreased 8-fold after 16 cycles of treatment with the tobramycin/furanone C-30 combination. Furthermore, microcalorimetry revealed changes in the metabolic activity of P. aeruginosa exposed to furanone C-30, tobramycin, and the combination. Whole-genome sequencing analysis of the evolved strains exposed to the combination identified mutations in mexT, fusA1 and parS, genes known to be involved in antibiotic resistance. In P. aeruginosa treated with furanone C-30 alone, a deletion in mexT was also observed. Our data indicate that furanone C-30 is not ‘evolution-proof’ and quickly becomes ineffective as a tobramycin potentiator.

scholarly journals Pangenome Analytics Reveal Two-Component Systems as Conserved Targets in ESKAPEE Pathogens

mSystems ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Akanksha Rajput ◽  
Yara Seif ◽  
Kumari Sonal Choudhary ◽  
Christopher Dalldorf ◽  
Saugat Poudel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Content Type ◽  
Vital Functions ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

ABSTRACT The two-component system (TCS) helps bacteria sense and respond to environmental stimuli through histidine kinases and response regulators. TCSs are the largest family of multistep signal transduction processes, and they are involved in many important cellular processes such as antibiotic resistance, pathogenicity, quorum sensing, osmotic stress, and biofilms. Here, we perform the first comprehensive study to highlight the role of TCSs as potential drug targets against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli) pathogens through annotation, mapping, pangenomic status, gene orientation, and sequence variation analysis. The distribution of the TCSs is group specific with regard to Gram-positive and Gram-negative bacteria, except for KdpDE. The TCSs among ESKAPEE pathogens form closed pangenomes, except for Pseudomonas aeruginosa. Furthermore, their conserved nature due to closed pangenomes might make them good drug targets. Fitness score analysis suggests that any mutation in some TCSs such as BaeSR, ArcBA, EvgSA, and AtoSC, etc., might be lethal to the cell. Taken together, the results of this pangenomic assessment of TCSs reveal a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. This study further suggests that the conserved features of TCSs might make them an attractive group of potential targets with which to address antibiotic resistance. IMPORTANCE The ESKAPEE pathogens are the leading cause of health care-associated infections worldwide. Two-component systems (TCSs) can be used as effective targets against pathogenic bacteria since they are ubiquitous and manage various vital functions such as antibiotic resistance, virulence, biofilms, quorum sensing, and pH balance, among others. This study provides a comprehensive overview of the pangenomic status of the TCSs among ESKAPEE pathogens. The annotation and pangenomic analysis of TCSs show that they are significantly distributed and conserved among the pathogens, as most of them form closed pangenomes. Furthermore, our analysis also reveals that the removal of the TCSs significantly affects the fitness of the cell. Hence, they may be used as promising drug targets against bacteria.

scholarly journals Novel Seleno- and Thio-Urea Containing Dihydropyrrol-2-One Analogues as Antibacterial Agents

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 321
Author(s):  
Shekh Sabir ◽  
Tsz Tin Yu ◽  
Rajesh Kuppusamy ◽  
Basmah Almohaywi ◽  
George Iskander ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Antibacterial Agents ◽  
Inhibitory Concentration ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Positive Bacterium ◽  
Quorum Sensing Inhibition ◽  
Drug Resistant Bacteria

The quorum sensing (QS) system in multi-drug-resistant bacteria such as P. aeruginosa is primarily responsible for the development of antibiotic resistance and is considered an attractive target for antimicrobial drug discovery. In this study, we synthesised a series of novel selenourea and thiourea-containing dihydropyrrol-2-one (DHP) analogues as LasR antagonists. The selenium DHP derivatives displayed significantly better quorum-sensing inhibition (QSI) activities than the corresponding sulphur analogues. The most potent analogue 3e efficiently inhibited the las QS system by 81% at 125 µM and 53% at 31 µM. Additionally, all the compounds were screened for their minimum inhibitory concentration (MIC) against the Gram-positive bacterium S. aureus, and interestingly, only the selenium analogues showed antibacterial activity, with 3c and 3e being the most potent with a MIC of 15.6 µM.

scholarly journals Bacteria and Their Antibiotic Resistance Profiles in Ambient Air in Accra, Ghana, February 2020: A Cross-Sectional Study

2021 ◽  
Vol 6 (3) ◽  
pp. 110
Author(s):  
Godfred Saviour Kudjo Azaglo ◽  
Mohammed Khogali ◽  
Katrina Hann ◽  
John Alexis Pwamang ◽  
Emmanuel Appoh ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Pathogenic Bacteria ◽  
Ambient Air ◽  
Cross Sectional Study ◽  
Bacillus Species ◽  
Resistant Bacteria ◽  
Cross Sectional ◽  
Antibiotic Resistant ◽  
Bacterial Counts ◽  
Inappropriate Use

Inappropriate use of antibiotics has led to the presence of antibiotic-resistant bacteria in ambient air. There is no published information about the presence and resistance profiles of bacteria in ambient air in Ghana. We evaluated the presence and antibiotic resistance profiles of selected bacterial, environmental and meteorological characteristics and airborne bacterial counts in 12 active air quality monitoring sites (seven roadside, two industrial and three residential) in Accra in February 2020. Roadside sites had the highest median temperature, relative humidity, wind speed and PM10 concentrations, and median airborne bacterial counts in roadside sites (115,000 CFU/m3) were higher compared with industrial (35,150 CFU/m3) and residential sites (1210 CFU/m3). Bacillus species were isolated in all samples and none were antibiotic resistant. There were, however, Pseudomonas aeruginosa, Escherichia coli, Pseudomonas species, non-hemolytic Streptococci, Coliforms and Staphylococci species, of which six (50%) showed mono-resistance or multidrug resistance to four antibiotics (penicillin, ampicillin, ciprofloxacin and ceftriaxone). There was a positive correlation between PM10 concentrations and airborne bacterial counts (rs = 0.72), but no correlations were found between PM10 concentrations and the pathogenic bacteria nor their antibiotic resistance. We call for the expansion of surveillance of ambient air to other cities of Ghana to obtain nationally representative information.

scholarly journals Antimicrobial Susceptibility of Lactic Acid Bacteria Strains of Potential Use as Feed Additives - The Basic Safety and Usefulness Criterion

2021 ◽  
Vol 8 ◽  
Author(s):  
Ilona Stefańska ◽  
Ewelina Kwiecień ◽  
Katarzyna Jóźwiak-Piasecka ◽  
Monika Garbowska ◽  
Marian Binek ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Lactic Acid ◽  
Lactic Acid Bacteria ◽  
Resistance Genes ◽  
Pathogenic Bacteria ◽  
Feed Additives ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Safety Criterion ◽  
Phenotypic Resistance

The spread of resistance to antibiotics is a major health concern worldwide due to the increasing rate of isolation of multidrug resistant pathogens hampering the treatment of infections. The food chain has been recognized as one of the key routes of antibiotic resistant bacteria transmission between animals and humans. Considering that lactic acid bacteria (LAB) could act as a reservoir of transferable antibiotic resistance genes, LAB strains intended to be used as feed additives should be monitored for their safety. Sixty-five LAB strains which might be potentially used as probiotic feed additives or silage inoculants, were assessed for susceptibility to eight clinically relevant antimicrobials by a minimum inhibitory concentration determination. Among antimicrobial resistant strains, a prevalence of selected genes associated with the acquired resistance was investigated. Nineteen LAB strains displayed phenotypic resistance to one antibiotic, and 15 strains were resistant to more than one of the tested antibiotics. The resistance to aminoglycosides and tetracyclines were the most prevalent and were found in 37 and 26% of the studied strains, respectively. Phenotypic resistance to other antimicrobials was found in single strains. Determinants related to resistance phenotypes were detected in 15 strains as follows, the aph(3″)-IIIa gene in 9 strains, the lnu(A) gene in three strains, the str(A)-str(B), erm(B), msr(C), and tet(M) genes in two strains and the tet(K) gene in one strain. The nucleotide sequences of the detected genes revealed homology to the sequences of the transmissible resistance genes found in lactic acid bacteria as well as pathogenic bacteria. Our study highlights that LAB may be a reservoir of antimicrobial resistance determinants, thus, the first and key step in considering the usefulness of LAB strains as feed additives should be an assessment of their antibiotic resistance. This safety criterion should always precede more complex studies, such as an assessment of adaptability of a strain or its beneficial effect on a host. These results would help in the selection of the best LAB strains for use as feed additives. Importantly, presented data can be useful for revising the current microbiological cut-off values within the genus Lactobacillus and Pediococcus.

scholarly journals Antimicrobial Resistance and Biofilm Formation of Pseudomonas aeruginosa

10.3823/846 ◽  
2020 ◽  
Vol 10 (2) ◽  
Author(s):  
Abdelraouf A Elmanama ◽  
Suhaila Al-Sheboul ◽  
Renad I Abu-Dan
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Quorum Sensing ◽  
Bacterial Adhesion ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Developmental Stages ◽  
Infection Site ◽  
Major Virulence Factor

Abstract Pseudomonas aeruginosa threatens patient’s care. It is considered as the most complicated health care associated pathogen to be eliminated from infection site. The biofilm forming ability of P. aeruginosa, being a major virulence factor for most pathogenic microorganism, protects it from host immunity and contribute to antibiotic resistance of this organism. It is estimated that about 80% of infectious diseases are due to biofilm mode of growth. Biofilm forming ability of bacteria imparts antimicrobial resistance that leads to many persistent and chronic bacterial infections. The world is becoming increasingly under the threat of entering the “post-antibiotic era”, an era in which the rate of death from bacterial infections is higher than from cancer. This review focus on P. aeruginosa biofilm forming ability; definition, developmental stages, and significance. In addition, the quorum sensing and the antibiotic resistance of this pathogen is discussed. Keywords: Biofilm; bacterial adhesion; Pseudomonas aeruginosa; antimicrobial resistance; quorum sensing.

scholarly journals Evolution under low antibiotic concentrations: a risk for the selection of Pseudomonas aeruginosa multidrug resistant mutants in nature

2021 ◽  
Author(s):  
Fernando Sanz-García ◽  
Sara Hernando-Amado ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Published Data ◽  
Natural Ecosystems ◽  
Clinical Value ◽  
Drug Concentrations ◽  
Resistant Mutants

ABSTRACTBACKGROUNDAntibiotic pollution of non-clinical environments might have a relevant impact on human health if resistant pathogens are selected. However, this potential risk is often overlooked, since drug concentrations in nature are usually below their minimal inhibitory concentrations (MICs). Albeit, antibiotic resistant bacteria can be selected even at sub-MIC concentrations, in a range that is dubbed the sub-MIC selective window, which depends on both the antibiotic and the pathogen.OBJECTIVESDetermine the sub-MIC selective windows of seven antibiotics of clinical relevance in the opportunistic pathogen Pseudomonas aeruginosa and evaluate the risk for selecting resistant mutants in nature, based on published data about the amount of antimicrobials detected in natural environments.METHODSWe conducted evolution experiments of P. aeruginosa PA14 in presence of sub-MIC concentrations of ceftazidime, amikacin, levofloxacin, ciprofloxacin, tetracycline, polymyxin B or imipenem, and measured drug susceptibility of the evolved populations.RESULTSSub-MIC selective window of quinolones was the largest, and the ones of polymyxin B and imipenem, the narrowest. Clinically relevant multidrug resistant (MDR) mutants (presenting MICs above EUCAST clinical breakpoints) arose within the sub-MIC selective windows of the majority of antibiotics tested, being these phenotypes probably mediated by efflux pumps′ activity.DISCUSSIONOur data show that the concentration of antibiotics reported in aquatic ecosystems -colonizable by P. aeruginosa- are, in occasions, higher than the ones able to select MDR mutants. This finding has implications for understanding the role of different ecosystems and conditions in the emergence of antibiotic resistance from a One-Health point of view. Further, it highlights the importance of delineating the sub-MIC selective windows for drugs of clinical value in pathogens with environmental niches, in order to evaluate the health risks due to antibiotic pollution of natural ecosystems and ultimately tackle antibiotic resistance.

Comparing antibiotic resistance in commensal and pathogenic bacteria isolated from wild-caught South Carolina shrimps vs. farm-raised imported shrimps

2007 ◽  
Vol 53 (7) ◽  
pp. 919-924 ◽  
Author(s):  
Kavitha Boinapally ◽  
Xiuping Jiang
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
South Carolina ◽  
Antimicrobial Resistance ◽  
Pathogenic Bacteria ◽  
Vibrio Vulnificus ◽  
Resistant Bacteria ◽  
Microbiological Analysis ◽  
Salmonella Spp ◽  
Plate Counts

The objective of this study was to assess and differentiate wild-caught South Carolina (SC) shrimps from imported shrimps on the basis of microbiological analysis. Seven wild-caught SC shrimp and 13 farm-raised imported shrimp samples were analyzed. Total plate counts from wild-caught shrimp samples ranged from 4.3 to 7.0 log10 CFU/g, whereas counts from imported shrimp samples ranged from 3.2 to 5.7 log10 CFU/g. There was no difference (P > 0.05) between total bacterial counts of wild-caught SC shrimp and farm-raised imported shrimp. However, the percentages of bacteria with reduced susceptibility towards ceftriaxone and tetracycline were higher (P < 0.05) for farm-raised shrimp than for wild-caught samples. Salmonella spp. detected only in one farm-raised sample was resistant to ampicillin, ceftriaxone, gentamicin, streptomycin, and trimethoprim. Vibrio vulnificus was detected in both wild-caught and farm-raised shrimp samples; however, only the isolate from farm-raised shrimp was resistant to nalidixic acid and trimethoprim. Escherichia coli detected in one wild-caught sample was resistant to ampicillin. Both Listeria spp. and Salmonella spp. were absent with wild-caught SC samples. Therefore, the presence of more ceftriaxone- and tetracycline-resistant bacteria and the observed antimicrobial resistance phenotypes of isolates from the imported shrimp may reflect the possible use of antibiotics in raising shrimp in those countries.

scholarly journals Antibiotic Resistance Evolution Is Contingent on the Quorum-Sensing Response in Pseudomonas aeruginosa

2019 ◽  
Vol 36 (10) ◽  
pp. 2238-2251 ◽  
Author(s):  
Sara Hernando-Amado ◽  
Fernando Sanz-García ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Wild Type ◽  
Resistance Mutations ◽  
Epistatic Interactions ◽  
Adaptive Mutations ◽  
Resistance Evolution ◽  
Evolutionary Trajectories

Abstract Different works have explored independently the evolution toward antibiotic resistance and the role of eco-adaptive mutations in the adaptation to a new habitat (as the infected host) of bacterial pathogens. However, knowledge about the connection between both processes is still limited. We address this issue by comparing the evolutionary trajectories toward antibiotic resistance of a Pseudomonas aeruginosa lasR defective mutant and its parental wild-type strain, when growing in presence of two ribosome-targeting antibiotics. Quorum-sensing lasR defective mutants are selected in P. aeruginosa populations causing chronic infections. Further, we observed they are also selected in vitro as a first adaptation for growing in culture medium. By using experimental evolution and whole-genome sequencing, we found that the evolutionary trajectories of P. aeruginosa in presence of these antibiotics are different in lasR defective and in wild-type backgrounds, both at the phenotypic and the genotypic levels. Recreation of a set of mutants in both genomic backgrounds (either wild type or lasR defective) allowed us to determine the existence of negative epistatic interactions between lasR and antibiotic resistance determinants. These epistatic interactions could lead to mutual contingency in the evolution of antibiotic resistance when P. aeruginosa colonizes a new habitat in presence of antibiotics. If lasR mutants are selected first, this would constraint antibiotic resistance evolution. Conversely, when resistance mutations (at least those studied in the present work) are selected, lasR mutants may not be selected in presence of antibiotics. These results underlie the importance of contingency and epistatic interactions in modulating antibiotic resistance evolution.

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