Efflux Pumps
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2022 ◽  
Vol 12 ◽  
Ying Zhou ◽  
Wenxiu Ai ◽  
Yanhua Cao ◽  
Yinjuan Guo ◽  
Xiaocui Wu ◽  

The rise and global dissemination of extensively drug-resistant (XDR) bacteria are often related to plasmid-borne mobile antimicrobial resistance genes. Notably, isolates having multiple plasmids are often highly resistant to almost all the antibiotics available. In this study, we characterized an extensively drug-resistant Klebsiella pneumoniae 1678, which exhibited high-level resistance to almost all the available antibiotics. Through whole-genome sequencing (WGS), more than 20 resistant elements and 5 resistant plasmids were observed. Notably, the tigecycline resistance of K. pneumoniae 1678 was not related to the plasmid-borne tetA gene but associated with the overexpression of AcrAB and OqxAB efflux pumps, according to the susceptibility results of tetA-transformant and the related mRNA quantification of RND efflux pumps. Except for tigecycline resistance, three plasmids, mediating resistance to colistin, Fosfomycin, and ceftazidime–avibactam, respectively, were focused. Detailed comparative genetic analysis showed that all these plasmids belonged to dominated epidemic plasmids, and harbored completed conjugation systems. Results of conjugation assay indicated that these three plasmids not only could transfer to E. coli J53 with high conjugation frequencies, respectively, but also could co-transfer to E. coli J53 effectively, which was additionally confirmed by the S1-PFGE plasmids profile. Moreover, multiple insertion sequences (IS) and transposons (Tn) were also found surrounding the vital resistant genes, which may form several novel mechanisms involved in the resistant determinants’ mobilization. Overall, we characterized and reported the uncommon co-existence and co-transferring of FosA3-, NDM-5, and MCR-1-encoding plasmids in a K. pneumoniae isolate, which may increase the risk of spread of these resistant phenotypes and needing great concern.

2021 ◽  
Vol 14 (4) ◽  
pp. 1905-1915
Michael Ofori ◽  
Cynthia Amaning Danquah ◽  
Selase Ativui ◽  
Peace Doe ◽  
Williams Adu Asamoah

Drug resistant tuberculosis remains one of the major challenges associated with treatment and management of tuberculosis (TB) in the public health system and in clinical settings. In 2020, the World Health Organization (WHO) estimated that about 186,772 people died from drug-resistant tuberculosis out of the 500000 reported cases and this is alarming. There is a pressing need from every angle in drug discovery to develop novel compounds that could possess diverse mechanisms of action to tackle drug-resistant tuberculosis. The Crinum asiaticum bulbs extract are used ethno medicinally to treat upper respiratory tract infections and as well as wound healing agent. The aim of this work is to investigate the in-vitro anti-tuberculosis effect of Crinum asiaticum bulbs extracts and to assess the inhibitory properties against bacteria efflux pumps expression and biofilm formation. The results obtained showed that the Crinum asiaticum bulbs extracts (CAE) were effective in inhibiting Mycobacterium smegmatis (NCTC 8159) and Mycobacterium aurum (NCTC 10437) with minimum inhibitory concentration (MIC) of 125 μg/ml and 250 μg/ml against M. smegmatis and M. aurum respectively. The CAE markedly inhibited the efflux pumps of both M. smegmatis and M. aurum from expressing with the chloroform extract producing the greatest inhibition. The CAE (ethanol, methanol, chloroform and hexane) significantly (***ρ˂0.005) inhibited M. smegmatis’ and M. aurum’s biofilm formation in-vitro. Among the various extracts of Crinum asiaticum, the chloroform extract exhibited the greatest inhibition against M. smegmatis and M. aurum biofilm formation with significance levels of ***ρ˂0.005 and ***ρ˂0.005. In conclusion the CAE has anti-tuberculosis effect and could tackle drug resistant TB as exhibited through the anti-efflux and anti-biofilm forming properties of the extract against the selected Mycobacterium species.

Antibiotics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 32
Reo Onishi ◽  
Katsumi Shigemura ◽  
Kayo Osawa ◽  
Young-Min Yang ◽  
Koki Maeda ◽  

Imipenemase-6 (IMP-6) type carbapenemase-producing Enterobacteriaceae is regarded as dangerous due to its unique lack of antimicrobial susceptibility. It is resistant to meropenem (MEPM) but susceptible to imipenem (IPM). In addition to carbapenemase, outer membrane porins and efflux pumps also play roles in carbapenem resistance by reducing the antimicrobial concentration inside cells. Extended-spectrum β-lactamase (ESBL) is transmitted with IMP-6 by the plasmid and broadens the spectrum of antimicrobial resistance. We collected 42 strains of IMP-6-producing Escherichia coli and conducted a molecular analysis of carbapenemase, ESBL, porin, efflux, and epidemiological characteristics using plasmid replicon typing. Among the 42 isolates, 21 strains were susceptible to IPM (50.0%) and 1 (2.4%) to MEPM. Seventeen strains (40.5%) co-produced CTX-M-2 type ESBL. We found that the relative expression of ompC and ompF significantly correlated with the MIC of IPM (p = 0.01 and p = 0.03, respectively). Sixty-eight% of CTX-M-2-non-producing strains had IncI1, which was significantly different from CTX-M-2-producing strains (p < 0.001). In conclusion, 50.0% of our IMP-6-producing strains were non-susceptible to IPM, which is different from the typical pattern and can be attributed to decreased porin expression. Further studies investigating other types of carbapenemase are warranted.

2021 ◽  
Vol 204 (1) ◽  
Janaína Esmeraldo Rocha ◽  
Thiago Sampaio de Freitas ◽  
Jayze da Cunha Xavier ◽  
Raimundo Luiz Silva Pereira ◽  
Francisco Nascimento Pereira ◽  

Q.C. Truong-Bolduc ◽  
Y. Wang ◽  
J. L. Reedy ◽  
J.M. Vyas ◽  
D.C. Hooper

Mupirocin induced expression of genes encoding efflux pumps NorA and MepA as well as a YFP fluorescence reporter of NorA. Mupirocin exposure also produced reduced susceptibility to pump substrates ciprofloxacin and chlorhexidine, a change that was dependent on intact norA and mepA , respectively.

2021 ◽  
Vol 3 (12) ◽  
Vartika Srivastava ◽  
Aijaz Ahmad

Background: Candida auris, a decade old Candida species, has been identified globally as a significant nosocomial multidrug resistant (MDR) pathogen responsible for causing invasive outbreaks. Biofilms and over expression of efflux pumps such as Major Facilitator Superfamily and ATP Binding Cassette are known to cause multidrug resistance in Candida species, including C. auris. Therefore, targeting these factors may prove an effective approach to combat MDR in C. auris. Methods: In this study, 25 clinical isolates of C. auris from different hospitals of South Africa were used. Antifungal susceptibility profile of all the isolates against commonly used drugs was determined following CLSI recommended guidelines. Rhodamine-6-G extracellular efflux and intracellular accumulation assays were used to study active drug efflux mechanism. We further studied the role of farnesol in modulating development of biofilms and drug efflux in C. auris. Down-regulation of biofilm- and efflux pump- associated genes by farnesol was also investigated. CLSM analysis for examining C. auris biofilm architecture among treated and untreated isolates. Results: Most of the isolates (twenty-two) were found resistant to FLZ whereas five were resistant to AmB. All the isolates were found capable of biofilm formation and ornamented with active drug efflux mechanism. The MIC for planktonic cells ranged from 62.5-125 mM and for sessile cells was 125 mM (0 h and 4 h biofilm) and 500 mM (12 h and 24 h biofilm), CLSM studies also confirmed these findings. Farnesol also blocked efflux pumps and down-regulated biofilm- and efflux pump- associated genes. Conclusion: Modulation of biofilm- and efflux pump- associated genes by farnesol represent a promising approach in combating C. auris infection.

2021 ◽  
Naíla Barbosa da Costa ◽  
Marie-Pier Hébert ◽  
Vincent Fugère ◽  
Yves Terrat ◽  
Gregor Fussmann ◽  

Agrochemicals often contaminate freshwater bodies, affecting microbial communities that underlie aquatic food webs. For example, Roundup, a widely-used glyphosate-based herbicide (GBH), has the potential to indirectly select for antibiotic resistant bacteria. Such cross-selection could occur, for example, if the same genes (e.g. encoding efflux pumps) confer resistance to both glyphosate and antibiotics. To test for cross-resistance in natural aquatic bacterial communities, we added Roundup to 1,000-L mesocosms filled with water from a pristine lake. Over 57 days, we tracked changes in bacterial communities with shotgun metagenomic sequencing, and annotated metagenome-assembled genomes (MAGs) for the presence of known antibiotic resistance genes (ARGs), plasmids, and resistance mutations in the enzyme targeted by glyphosate (enolpyruvyl-shikimate-3-phosphate synthase; EPSPS). We found that high doses of GBH significantly increased ARG frequency and selected for multidrug efflux pumps in particular. The relative abundance of MAGs after a high dose of GBH was predictable based on the number of ARGs encoded in their genomes (17% of variation explained) and, to a lesser extent, by resistance mutations in EPSPS (2% of variation explained). Together, these results indicate that GBHs have the potential to cross-select for antibiotic resistance in natural freshwater bacteria.

Nisha Mahey ◽  
Rushikesh Tambat ◽  
Nishtha Chandal ◽  
Dipesh Kumar Verma ◽  
Krishan Gopal Thakur ◽  

Staphylococcus aureus is a frequent pathogen bacterium and the predominant cause of worsened nosocomial infections. Efflux pumps contribute to drug efflux and are reportedly associated with biofilm formation, thereby promoting difficult-to-treat biofilm-associated S. aureus infections.

2021 ◽  
Ryan Kerr ◽  
Sara Jabbari ◽  
Jessica M A Blair ◽  
Iain Johnston

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalisable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Further, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1502
Abolfazl Dashtbani-Roozbehani ◽  
Melissa H. Brown

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

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