scholarly journals Substitutions in SurA and BamA Lead to Reduced Susceptibility to Broad Range Antibiotics in Gonococci

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1312
Author(s):  
Ivan Bodoev ◽  
Maja Malakhova ◽  
Julia Bespyatykh ◽  
Dmitry Bespiatykh ◽  
Georgij Arapidi ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Efflux Pump ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Antibiotic Resistant ◽  
Efflux Pump Inhibition ◽  
Periplasmic Chaperone ◽  
Quantitative Changes ◽  
Periplasmic Chaperones

There is growing concern about the emergence and spread of multidrug-resistant Neisseria gonorrhoeae. To effectively control antibiotic-resistant bacterial pathogens, it is necessary to develop new antimicrobials and to understand the resistance mechanisms to existing antibiotics. In this study, we discovered the unexpected onset of drug resistance in N. gonorrhoeae caused by amino acid substitutions in the periplasmic chaperone SurA and the β-barrel assembly machinery component BamA. Here, we investigated the i19.05 clinical isolate with mutations in corresponding genes along with reduced susceptibility to penicillin, tetracycline, and azithromycin. The mutant strain NG05 (surAmut bamAmut, and penAmut) was obtained using the pan-susceptible n01.08 clinical isolate as a recipient in the transformation procedure. Comparative proteomic analysis of NG05 and n01.08 strains revealed significantly increased levels of other chaperones, Skp and FkpA, and some transport proteins. Efflux pump inhibition experiments demonstrated that the reduction in sensitivity was achieved due to the activity of efflux pumps. We hypothesize that the described mutations in the surA and bamA genes cause the qualitative and quantitative changes of periplasmic chaperones, which in turn alters the function of synthesized cell envelope proteins.

Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition

2021 ◽  
Vol 4 (9) ◽  
pp. 9799-9810
Author(s):  
Ioanna Eleftheriadou ◽  
Kleoniki Giannousi ◽  
Efthymia Protonotariou ◽  
Lemonia Skoura ◽  
Minas Arsenakis ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Efflux Pump Inhibition

scholarly journals Bioactive constituents with antibacterial, resistance modulation, anti-biofilm formation and efflux pump inhibition properties from Aidia genipiflora stem bark

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daniel Anokwah ◽  
Evelyn Asante-Kwatia ◽  
Abraham Y. Mensah ◽  
Cynthia Amaning Danquah ◽  
Benjamin K. Harley ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Efflux Pump ◽  
Ethyl Acetate Fraction ◽  
Stem Bark ◽  
Resistance Mechanisms ◽  
Bioactive Constituents ◽  
Biofilm Inhibition ◽  
E Coli ◽  
Efflux Pump Inhibition ◽  
Oleanonic Acid

Abstract Background Antimicrobial resistance is a global health challenge. The involvement of bacterial biofilms and efflux pumps in the development of multidrug resistance (MDR) is well established. Medicinal plants have been proposed as alternatives for combating MDR focusing on their bioactive constituents with resistance modulatory activities. This study was aimed at investigating the stem bark of Aidia genipiflora for bioactive constituents with anti-biofilm, efflux pump inhibition and resistance modulatory activities. Method The crude methanol extract was purified by column chromatography and isolated compounds characterized by mass and nuclear magnetic resonance spectrometry. Antibacterial activity was determined by the High-throughput spot culture growth inhibition and the broth micro-dilution assay. The ethidium bromide accumulation assay was used to determine efflux pump inhibition property. Biofilm inhibition was determined in a microplate crystal violet retention assay. Results Purification of the ethyl acetate fraction led to the isolation of oleanonic acid (1), 4-hydroxy cinnamic acid docosyl ester (2), β-stigmasterol/β-sitosterol (mixture 3a/b) and D-mannitol (4). The minimum inhibitory concentrations (MICs) ranged from 250 to > 500 μg/mL for extracts and fractions and from 15 to 250 μg/mL for compounds. In the presence of sub-inhibitory concentrations of the compounds, the MIC of amoxicillin against E. coli (20 μg/mL) and P. aeruginosa (320 μg/mL) was reduced by 32 and 10 folds respectively. The whole extract demonstrated anti-biofilm formation and efflux pump inhibition in E. coli, S. aureus and P. aeruginosa. The sterol mixture (3a/b) at concentration of 100 μg/mL caused the highest inhibition (73%) of biofilm formation in S. aureus. Oleanonic acid (1) demonstrated remarkable efflux pump inhibition at MIC of 7.8 μg/mL in E. coli better than the standard drugs verapamil and chlorpromazine. Conclusion This study confirms the prospects of A. genipiflora as a source of new antibacterial agents and adjuvants that could interact with some resistance mechanisms in bacteria to enhance the activity of hitherto ineffective antibiotics. “A small portion of the study has been presented in a conference in the form of poster”.

Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Balaram Khamari ◽  
Prakash Kumar ◽  
Bulagonda Eswarappa Pradeep
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Treatment Options ◽  
Strong Association ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

scholarly journals Conservation of resistance nodulation cell division efflux pump mediated antibiotic resistance in Burkholderia cepacia complex and Burkholderia pseudomallei complex species

2021 ◽  
Author(s):  
Nawarat Somprasong ◽  
Jinhee Yi ◽  
Carina M. Hall ◽  
Jessica R. Webb ◽  
Jason W. Sahl ◽  
...  
Keyword(s):  
Cell Division ◽  
Burkholderia Cepacia ◽  
Burkholderia Pseudomallei ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Burkholderia Cepacia Complex ◽  
Complex Species ◽  
Functional Studies ◽  
Rnd Efflux Pump

Burkholderia cepacia complex (Bcc) and Burkholderia pseudomallei complex (Bpc) species include pathogens that are typically multidrug resistant. Dominant intrinsic and acquired multidrug resistance mechanisms are efflux mediated by pumps of the resistance nodulation cell division (RND) family. From comparative bioinformatic and, in many instances, functional studies we infer that RND pump-based resistance mechanisms are conserved in Burkholderia . We propose to use these findings as a foundation for adoption of a uniform RND efflux pump nomenclature.

scholarly journals Environment Shapes the Accessible Daptomycin Resistance Mechanisms in Enterococcus faecium

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Amy G. Prater ◽  
Heer H. Mehta ◽  
Abigael J. Kosgei ◽  
William R. Miller ◽  
Truc T. Tran ◽  
...  
Keyword(s):  
Enterococcus Faecium ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Clinical Strain ◽  
Content Type ◽  
Component Cell ◽  
Evolutionary Trajectories ◽  
High Level ◽  
Cell Envelopes

ABSTRACT Daptomycin binds to bacterial cell membranes and disrupts essential cell envelope processes, leading to cell death. Bacteria respond to daptomycin by altering their cell envelopes to either decrease antibiotic binding to the membrane or by diverting binding away from septal targets. In Enterococcus faecalis, daptomycin resistance is typically coordinated by the three-component cell envelope stress response system, LiaFSR. Here, studying a clinical strain of multidrug-resistant Enterococcus faecium containing alleles associated with activation of the LiaFSR signaling pathway, we found that specific environments selected for different evolutionary trajectories, leading to high-level daptomycin resistance. Planktonic environments favored pathways that increased cell surface charge via yvcRS upregulation of dltABCD and mprF, causing a reduction in daptomycin binding. Alternatively, environments favoring complex structured communities, including biofilms, evolved both diversion and repulsion strategies via divIVA and oatA mutations, respectively. Both environments subsequently converged on cardiolipin synthase (cls) mutations, suggesting the importance of membrane modification across strategies. Our findings indicate that E. faecium can evolve diverse evolutionary trajectories to daptomycin resistance that are shaped by the environment to produce a combination of resistance strategies. The accessibility of multiple and different biochemical pathways simultaneously suggests that the outcome of daptomycin exposure results in a polymorphic population of resistant phenotypes, making E. faecium a recalcitrant nosocomial pathogen.

scholarly journals Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 119 ◽  
Author(s):  
Carole Ayoub Moubareck ◽  
Dalal Hammoudi Halat
Keyword(s):  
Acinetobacter Baumannii ◽  
Virulence Factors ◽  
Efflux Pump ◽  
Iron Acquisition ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Biofilm Production ◽  
Resistant Phenotype ◽  
Severe Infections ◽  
Hydrolyzing Enzymes

Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.

scholarly journals IS5Element Integration, a Novel Mechanism for RapidIn VivoEmergence of Tigecycline Nonsusceptibility in Klebsiella pneumoniae

2014 ◽  
Vol 58 (10) ◽  
pp. 6151-6156 ◽  
Author(s):  
Lindsey E. Nielsen ◽  
Erik C. Snesrud ◽  
Fatma Onmus-Leone ◽  
Yoon I. Kwak ◽  
Ricardo Avilés ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Insertion Element ◽  
Content Type ◽  
Reverse Transcription Quantitative Pcr ◽  
Antimicrobial Susceptibility Tests ◽  
Susceptibility Tests

ABSTRACTTigecycline nonsusceptibility is concerning because tigecycline is increasingly relied upon to treat carbapenem- or colistin-resistant organisms. InEnterobacteriaceae, tigecycline nonsusceptibility is mediated by the AcrAB-TolC efflux pump, among others, and pump activity is often a downstream effect of mutations in their transcriptional regulators, cognate repressor genes, or noncoding regions, as demonstrated inEnterobacteriaceaeandAcinetobacterisolates. Here, we report the emergence of tigecycline nonsusceptibility in a longitudinal series of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Klebsiella pneumoniaeisolates collected during tigecycline therapy and the elucidation of its resistance mechanisms. Clinical isolates were recovered prior to and during tigecycline therapy of a 2.5-month-old Honduran neonate. Antimicrobial susceptibility tests to tigecycline determined that the MIC increased from 1 to 4 μg/ml prior to the completion of tigecycline therapy. Unlike other studies, we did not find increased expression oframA,ramR,oqxA,acrB,marA, orrarAgenes by reverse transcription-quantitative PCR (qRT-PCR). Whole-genome sequencing revealed an IS5insertion element in nonsusceptible isolates 85 bp upstream of a putative efflux pump operon, here namedkpgABC, previously unknown to be involved in resistance. Introduction of thekpgABCgenes in a non-kpgABCbackground increased the MIC of tigecycline 4-fold and is independent of a functional AcrAB-TolC pump. This is the first report to propose a function forkpgABCand identify an insertion element whose presence correlated with thein vivodevelopment of tigecycline nonsusceptibility inK. pneumoniae.

scholarly journals Two resistance nodulation division-family efflux pumps inChromobacteriumspecies and their role in antibiotic resistance and tolerance

2019 ◽  
Author(s):  
Saida Benomar ◽  
Kara C Evans ◽  
Robert L Unckless ◽  
Josephine R Chandler
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Bacterial Species ◽  
Efflux Pumps ◽  
Resistance Mechanisms ◽  
Antibiotic Resistant ◽  
Burkholderia Thailandensis ◽  
New Information ◽  
Resistance Nodulation Division ◽  
Culture Growth

ABSTRACTVery little is known of the antibiotic resistance mechanisms of members of theChromobacteriumgenus. In previous studies ofChromobacterium subtsugae(formerlyC. violaceum) strain CV017, we identified a resistance nodulation division (RND)-family efflux pump (CdeAB-OprM). Here, we show thecdeAB-oprMgenes are widely distributed in members of theChromobacteriumgenus. We use antimicrobial susceptibility testing with a CV017cdeAB-oprMmutant to show the products of these genes confers resistance to a variety of antibiotics including ciprofloxacin, a clinically important antibiotic. We also identified a related RND-family pump,cseAB-oprN, in the genome of CV017 and otherC. subtsugaespecies, that is not present in other members of theChromobacteriumgenus. We demonstrate that CdeAB-OprM and CseAB-OprN are both transcriptionally induced in CV017 cells treated with sub-lethal antibiotic concentrations and they are important for induction of tolerance to different antibiotics. While CdeAB-OprM has a broad antibiotic specificity, the CseAB-OprN system is highly specific for a ribosome-targeting antibiotic produced by the saprophytic bacteriumBurkholderia thailandensis,bactobolin. Finally, we use a previously developedB. thailandensis-C. subtsugaeCV017 co-culture model to demonstrate that adding sub-lethal bactobolin at the beginning of co-culture growth increases the ability of CV017 to compete withB. thailandensisin a manner that is dependent on the CseAB-OprN system. Our results provide new information on the antibiotic resistance mechanisms ofChromobacteriumspecies and highlight the importance of efflux pumps during competition with other bacterial species.IMPORTANCEThis study describes two closely related efflux pumps in members of theChromobacteriumgenus, which includes opportunistic but often-fatal pathogens and species with highly versatile metabolic capabilities. Efflux pumps remove antibiotics from the cell and are important for antibiotic resistance. One of these pumps is broadly distributed in theChromobacteriumgenus and increases resistance to clinically relevant antibiotics. The other efflux pump is present only inChromobacterium subtsugaeand is highly specific for bactobolin, an antibiotic produced by the soil saprophyteBurkholderia thailandensis. We demonstrate these pumps can be activated to increase resistance by their antibiotic substrates, and that this activation is important forC. subtsugaeto survive in a laboratory competition experiment withB. thailandensis.These results have implications for managing antibiotic-resistantChromobacteriuminfections, bioengineering ofChromobacteriumspecies, and for understanding the evolution of efflux pumps.

scholarly journals Emergence of Multidrug-Resistant Uropathogens harboring ESBL, Carbapenem, Aminoglycosides and AmpC resistant genes from Northern India

2018 ◽  
Author(s):  
Varsha Rani Gajamer ◽  
Amitabha Bhattacharjee ◽  
Deepjyoti Paul ◽  
Birson Ingti ◽  
Arunabha Sarkar ◽  
...  
Keyword(s):  
Resistance Gene ◽  
Antibiotic Resistance Gene ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Aminoglycoside Resistance ◽  
Antibiotic Resistant ◽  
Northern India ◽  
Carbapenem Resistant ◽  
Resistant Genes ◽  
Esbl Producers

ABSTRACTExtended-spectrum β-lactamase (ESBL) producing bacteria acts as a serious threat, and its co-existence with other antibiotic resistant gene makes the clinical scenario worse nowadays. Therefore in this study, we investigated the occurrence of ESBL genes coexisting with carbapenem, AmpC and aminoglycoside resistance gene in uropathogens. Out of 1516 urine samples, 454 showed significant bacteriuria with a prevalence rate of 29.94 %. Escherichia coli (n=340) were found to be the most predominant uropathogen followed by Klebsiella pneumoniae (n=92), Pseudomonas aeruginosa (n=10) and Proteus mirabilis (n=9). Among the total uropathogens, sixty-three ESBL-producers were identified which included blaCTX-M-15 (n=32), followed by blaCTX-M-15 + blaOXA-2 (n=15), blaCTX-M-15 + blaOXA-2 + blaTEM (n=6), blaOXA-2 (n=5), blaOXA-2 + blaSHV-76 (n=1), blaTEM+SHV-76 (n= 1) and blaTEM (n=1). All ESBL genes were found on plasmid incompatibility types: HI1, I1, FIA+FIB, FIA and Y and were horizontally transferable. Among 63 ESBL-producers, 59 isolates harboured carbapenem-resistant genes which included blaNDM-5 (n=48), blaNDM-5 + blaOXA-48 (n=5), blaNDM-5 + blaIMP (n=5) and blaNDM-5 + blaIMP + blaVIM (n=1). The ESBL producing uropathogens also harbored 16S rRNA methylase genes which included rmtB (n=9), rmtA (n=4), rmtC (n=1) and ArmA (n=1) followed by AmpC genes which includes CIT (n=8) and DHA-1 (n=1) genes. Imipenem and gentamicin were found to be more effective. We speculating, this is the first report showing the prevalence of multidrug-resistant uropathogens in this area demanding regular surveillance for such resistance mechanisms which will be useful for health personnel to treat ESBL infection and its co-existence with another antibiotic resistance gene.

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