Bacterial Multidrug Efflux Proteins: A Major Mechanism of Antimicrobial Resistance

Ahmad, Irshad; Nawaz, Nighat; Dermani, Fatemeh Karimi; Kohlan, Alisa Khodadadi; Saidijam, Massoud; Patching, Simon G.

doi:10.2174/1389450119666180426103300

Cited by 19 publications

(14 citation statements)

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“…Gram-negative bacteria are intrinsically more resistant to antimicrobial compounds than Gram-positive organisms due to (i) the requirement for penetration of both the negatively charged outer and lipophilic inner membranes, (ii) stringent transcriptional and post-transcriptional control of porin expression in the outer membrane, and (iii) expression of multi-drug efflux pumps [4–6]. As a result of these barriers to the entry of small molecules into cells, many bioactive compounds discovered in cell-free, targeted screens do not retain their activity in whole cell assays [7].…”

Section: Introductionmentioning

confidence: 99%

A high-throughput, whole cell assay to identify compounds active against carbapenem-resistant Klebsiella pneumoniae

Liao

Mevers

et al. 2018

PLoS ONE

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Enteric Gram-negative rods (GNR), which are frequent causes of community-acquired and nosocomial infections, are increasingly resistant to the antibiotics in our current armamentarium. One solution to this medical dilemma is the development of novel classes of antimicrobial compounds. Here we report the development of a robust, whole cell-based, high-throughput metabolic assay that detects compounds with activity against carbapenem-resistant Klebsiella pneumoniae. We have used this assay to screen approximately 8,000 fungal extracts and 50,000 synthetic compounds with the goal of identifying extracts and compounds active against a highly resistant strain of Klebsiella pneumoniae. The primary screen identified 43 active fungal extracts and 144 active synthetic compounds. Patulin, a known fungal metabolite and inhibitor of bacterial quorum sensing and alanine racemase, was identified as the active component in the most potent fungal extracts. We did not study patulin further due to previously published evidence of toxicity. Three synthetic compounds termed O06, C17, and N08 were chosen for further study. Compound O06 did not have significant antibacterial activity but rather interfered with sugar metabolism, while compound C17 had only moderate activity against GNRs. Compound N08 was active against several resistant GNRs and showed minimal toxicity to mammalian cells. Preliminary studies suggested that it interferes with protein expression. However, its direct application may be limited by susceptibility to efflux and a tendency to form aggregates in aqueous media. Rapid screening of 58,000 test samples with identification of several compounds that act on CR-K. pneumoniae demonstrates the utility of this screen for the discovery of drugs active against this highly resistant GNR.

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Section: Introductionmentioning

confidence: 99%

A high-throughput, whole cell assay to identify compounds active against carbapenem-resistant Klebsiella pneumoniae

Liao

Mevers

et al. 2018

PLoS ONE

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“…Interestingly, two putative transmembrane proteins up-regulated in T9.386 share similarity with multidrug efflux transporters of the MATE-like (Mbov_0193) and MFS-3 (Mbov_0756) superfamilies. These multidrug transporters were recently associated with bacterial resistance to antimicrobials [40][41][42][43], suggesting that Mbov_0328/0327 might also influence M. bovis susceptibility to antibiotics, in addition to securing survival in cell culture. Altogether these data indicate that Mbov_0328/0327 disruption may induce important biological modifications in M. bovis.…”

Section: Mbov_0328/0327 Disruption In M Bovis Induces Global Changesmentioning

confidence: 99%

An emerging role for cyclic dinucleotide phosphodiesterase and nanoRNase activities in Mycoplasma bovis: Securing survival in cell culture

et al. 2020

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Mycoplasmas are host-restricted prokaryotes with a nearly minimal genome. To overcome their metabolic limitations, these wall-less bacteria establish intimate interactions with epithelial cells at mucosal surfaces. The alarming rate of antimicrobial resistance among pathogenic species is of particular concern in the medical and veterinary fields. Taking advantage of the reduced mycoplasma genome, random transposon mutagenesis was combined with high-throughput screening in order to identify key determinants of mycoplasma survival in the host-cell environment and potential targets for drug development. With the use of the ruminant pathogen Mycoplasma bovis as a model, three phosphodiesterases of the DHH superfamily were identified as essential for the proliferation of this species under cell culture conditions, while dispensable for axenic growth. Despite a similar domain architecture, recombinant Mbov_0327 and Mbov_0328 products displayed different substrate specificities. While rMbovP328 protein exhibited activity towards cyclic dinucleotides and nanoR-NAs, rMbovP327 protein was only able to degrade nanoRNAs. The Mbov_0276 product was identified as a member of the membrane-associated GdpP family of phosphodiesterases that was found to participate in cyclic dinucleotide and nanoRNA degradation, an activity which might therefore be redundant in the genome-reduced M. bovis. Remarkably, all these enzymes were able to convert their substrates into mononucleotides, and medium supplementation with nucleoside monophosphates or nucleosides fully restored the capacity of a Mbov_0328/0327 knockout mutant to grow under cell culture conditions. Since mycoplasmas are unable to synthesize DNA/RNA precursors de novo, cyclic dinucleotide and nanoRNA degradation are likely contributing to the survival of M. bovis by securing the recycling of purines and pyrimidines. These results point toward proteins of the DHH

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“…MFS is composed of secondary transporters that use the electrochemical gradient of protons across the cell membrane to catalyze the export of substrates, such as drugs, toxic compounds and antibiotics [15][16][17]. MFS is classified into 82 families according to the transporter classification system (http://www.tcdb.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of ionic-liquid tolerant Bacillus amyloliquefaciens CMW1 and identification of a novel efflux pump

Kurata

Aoki

Fukuta

et al. 2021

Biotechnology & Biotechnological Equipment

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Bacteria that exhibit ionic-liquid (IL) tolerance are useful in chemical industries using renewable carbon sources pre-treated by ILs to produce biofuels and fine chemicals. An IL, 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), has a remarkable ability to solubilize wood components, whereas [BMIM]Cl inhibits the growth of various bacterial hosts useful for bioconversion. We previously isolated a 10% [BMIM]Cl-tolerant bacterium Bacillus amyloliquefaciens CMW1. Here we report novel mechanisms of tolerance to [BMIM]Cl in strain CMW1 and a novel major facilitator superfamily transporter coded by an ionic-liquid tolerance (ILT) gene. First, using CMW1 cells grown in the presence or absence of 10% [BMIM]Cl, whole-transcriptome analysis and differentially expressed gene analysis were performed. Probable mechanisms of tolerance to [BMIM]Cl include the uptake of osmoprotectants from the culture medium toward CMW1 cells and the export of [BMIM] cations that accumulated in CMW1 cells. The finding represents a first step in elucidation of the mechanisms of IL resistance in Gram-positive bacteria. Second, we conferred tolerance to 5% [BMIM]Cl on [BMIM]Cl-susceptible Brevibacillus choshinensis using ILT gene. This finding provides a notable basis for engineering IL-tolerant bacterial hosts that are applicable for the effective and sustainable production of industrially important chemicals.

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Bacterial Multidrug Efflux Proteins: A Major Mechanism of Antimicrobial Resistance

Cited by 19 publications

References 0 publications

A high-throughput, whole cell assay to identify compounds active against carbapenem-resistant Klebsiella pneumoniae

A high-throughput, whole cell assay to identify compounds active against carbapenem-resistant Klebsiella pneumoniae

An emerging role for cyclic dinucleotide phosphodiesterase and nanoRNase activities in Mycoplasma bovis: Securing survival in cell culture

Transcriptome analysis of ionic-liquid tolerant Bacillus amyloliquefaciens CMW1 and identification of a novel efflux pump

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