AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Jang, Soojin

doi:10.5483/bmbrep.2023-0070

Cited by 21 publications

(8 citation statements)

References 97 publications

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“…Efflux pumps are important membrane proteins that play a crucial role as defense mechanisms by actively exporting harmful substances, such as antibiotics, detergents, and heavy metals ( Jang, 2023 ). In our study, all of the isolates studied harbored acrA , encoding a subunit that functions as an adapter protein linked to AcrB, and TolC outer membrane channel proteins.…”

Section: Discussionmentioning

confidence: 99%

First report of coexistence of blaKPC-2 and blaNDM-1 in carbapenem-resistant clinical isolates of Klebsiella aerogenes in Brazil

Rodrigues,

Nunes,

Soares

et al. 2024

Front. Microbiol.

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Klebsiella aerogenes is an important opportunistic pathogen with the potential to develop resistance against last-line antibiotics, such as carbapenems, limiting the treatment options. Here, we investigated the antibiotic resistance profiles of 10 K. aerogenes strains isolated from patient samples in the intensive-care unit of a Brazilian tertiary hospital using conventional PCR and a comprehensive genomic characterization of a specific K. aerogenes strain (CRK317) carrying both the blaKPC-2 and blaNDM-1 genes simultaneously. All isolates were completely resistant to β-lactam antibiotics, including ertapenem, imipenem, and meropenem with differencing levels of resistance to aminoglycosides, quinolones, and tigecycline also observed. Half of the strains studied were classified as multidrug-resistant. The carbapenemase-producing isolates carried many genes of interest including: β-lactams (blaNDM-1, blaKPC-2, blaTEM-1, blaCTX-M-1 group, blaOXA-1 group and blaSHVvariants in 20-80% of the strains), aminoglycoside resistance genes [aac(6’)-Ib and aph(3’)-VI, 70 and 80%], a fluoroquinolone resistance gene (qnrS, 80%), a sulfonamide resistance gene (sul-2, 80%) and a multidrug efflux system transporter (mdtK, 70%) while all strains carried the efflux pumps Acr (subunit A) and tolC. Moreover, we performed a comprehensive genomic characterization of a specific K. aerogenes strain (CRK317) carrying both the blaKPC-2 and blaNDM-1 genes simultaneously. The draft genome assembly of the CRK317 had a total length of 5,462,831 bp and a GC content of 54.8%. The chromosome was found to contain many essential genes. In silico analysis identified many genes associated with resistance phenotypes, including β-lactamases (blaOXA-9, blaTEM-1, blaNDM-1, blaCTX-M-15, blaAmpC-1, blaAmpC-2), the bleomycin resistance gene (bleMBL), an erythromycin resistance methylase (ermC), aminoglycoside-modifying enzymes [aac(6’)-Ib, aadA/ant(3”)-Ia, aph(3’)-VI], a sulfonamide resistance enzyme (sul-2), a chloramphenicol acetyltransferase (catA-like), a plasmid-mediated quinolone resistance protein (qnrS1), a glutathione transferase (fosA), PEtN transferases (eptA, eptB) and a glycosyltransferase (arnT). We also detected 22 genomic islands, eight families of insertion sequences, two putative integrative and conjugative elements with a type IV secretion system, and eight prophage regions. This suggests the significant involvement of these genetic structures in the dissemination of antibiotic resistance. The results of our study show that the emergence of carbapenemase-producing K. aerogenes, co-harboring blaKPC-2 and blaNDM-1, is a worrying phenomenon which highlights the importance of developing strategies to detect, prevent, and control the spread of these microorganisms.

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Section: Discussionmentioning

confidence: 99%

First report of coexistence of blaKPC-2 and blaNDM-1 in carbapenem-resistant clinical isolates of Klebsiella aerogenes in Brazil

Rodrigues,

Nunes,

Soares

et al. 2024

Front. Microbiol.

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“…The periplasmic lipoprotein, AcrA, is classified as a fusion protein that bridges the outer and inner membranes [ 35 ]. The AcrB is a membrane protein located in the cytoplasmic membrane, and the TolC is an outer membrane protein [ 36 , 37 ]. Together they form AcrAB-TolC tripartite efflux pump system ( Figure 3 A).…”

Section: Discussionmentioning

confidence: 99%

“…PAβN is a synthetic efflux pump inhibitor that counteracts the activity of RND family efflux pumps [ 40 ]. The modified dipeptide-amide inhibits antibiotic efflux through the AcrAB-TolC system [ 37 ]. A computational simulation showed that PAβN binds to AcrB and inhibits efflux pumps at several residues [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the expression levels of acrA , acrB , and tolC were overexpressed in ST CIP ( Figure 2 ). The AcrAB-TolC efflux pump could actively extrude ciprofloxacin out of the bacterial cells, resulting in antibiotic resistance development [ 37 ]. The increase in ramA expression contributes to the enhanced efflux pump activity by regulating the expression of acrA , acrB , and tolC in Salmonella spp.…”

Section: Discussionmentioning

confidence: 99%

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Ciprofloxacin and Tetracycline Resistance Cause Collateral Sensitivity to Aminoglycosides in Salmonella Typhimurium

Hasan,

Wang,

Ahn

2023

Antibiotics

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The objective of this study was to evaluate collateral sensitivity and cross-resistance of antibiotic-induced resistant Salmonella Typhimurium to various antibiotics. S. Typhimurium ATCC 19585 (STWT) was exposed to ciprofloxacin, gentamicin, kanamycin, and tetracycline to induce antibiotic resistance, respectively, assigned as STCIP, STGEN, STKAN, and STTET. The susceptibilities of the antibiotic-induced resistant mutants to cefotaxime, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, polymyxin B, streptomycin, tetracycline, and tobramycin were determined in the absence and presence of CCCP and PAβN. STCIP showed the cross-resistance to tetracycline and collateral sensitivity to gentamicin (1/2 fold) and kanamycin (1/4 fold). STTET was also cross-resistant to ciprofloxacin (128-fold) and collateral sensitive to gentamicin (1/4-fold) and kanamycin (1/8-fold). The cross-resistance and collateral sensitivity of STCIP and STTET were associated with the AcrAB-TolC efflux pump and outer membrane porin proteins (OmpC). This study provides new insight into the collateral sensitivity phenomenon, which can be used for designing effective antibiotic treatment regimens to control antibiotic-resistant bacteria.

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“…The active efflux pump in gram-negative bacteria consists of three components: an outer membrane protein, a membrane fusion protein, and an efflux protein or transporter on the inner membrane. The RND efflux pump AcrAB-TolC, which is composed of a periplasmic fusion protein AcrA, a plasma membrane transporter AcrB, and an outer membrane channel protein TolC, plays an important role in the process of multidrug resistance in E. coli [53]. Before the drug acts on the intracellular target site, it binds to the plasma membrane transporter AcrB and is expelled from the cell through AcrA and the outer membrane channel TolC.…”

Section: Reduction In Antibiotic Intracellular Accumulationmentioning

confidence: 99%

The Combination of Antibiotic and Non-Antibiotic Compounds Improves Antibiotic Efficacy against Multidrug-Resistant Bacteria

Xiao,

Li,

Sun

2023

IJMS

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Bacterial antibiotic resistance, especially the emergence of multidrug-resistant (MDR) strains, urgently requires the development of effective treatment strategies. It is always of interest to delve into the mechanisms of resistance to current antibiotics and target them to promote the efficacy of existing antibiotics. In recent years, non-antibiotic compounds have played an important auxiliary role in improving the efficacy of antibiotics and promoting the treatment of drug-resistant bacteria. The combination of non-antibiotic compounds with antibiotics is considered a promising strategy against MDR bacteria. In this review, we first briefly summarize the main resistance mechanisms of current antibiotics. In addition, we propose several strategies to enhance antibiotic action based on resistance mechanisms. Then, the research progress of non-antibiotic compounds that can promote antibiotic-resistant bacteria through different mechanisms in recent years is also summarized. Finally, the development prospects and challenges of these non-antibiotic compounds in combination with antibiotics are discussed.

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AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Cited by 21 publications

References 97 publications

First report of coexistence of blaKPC-2 and blaNDM-1 in carbapenem-resistant clinical isolates of Klebsiella aerogenes in Brazil

First report of coexistence of blaKPC-2 and blaNDM-1 in carbapenem-resistant clinical isolates of Klebsiella aerogenes in Brazil

Ciprofloxacin and Tetracycline Resistance Cause Collateral Sensitivity to Aminoglycosides in Salmonella Typhimurium

The Combination of Antibiotic and Non-Antibiotic Compounds Improves Antibiotic Efficacy against Multidrug-Resistant Bacteria

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