Multidrug Resistance Efflux Pumps in Acinetobacter spp.: An Update

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00514-21 ◽

2021 ◽

Author(s):

Vanessa Kornelsen ◽

Ayush Kumar

Keyword(s):

Multidrug Resistance ◽

Antimicrobial Resistance ◽

Bacterial Species ◽

Clinical Importance ◽

Efflux Pumps ◽

Major Facilitator Superfamily ◽

Small Multidrug Resistance ◽

Resistance Nodulation Division ◽

Rnd Efflux Pumps ◽

Major Facilitator

Acinetobacter spp. have become of increased clinical importance as studies have shown the antimicrobial resistant potential of these species. Efflux pumps can lead to reduced susceptibility to a variety of antibiotics and are present in large number across Acinetobacter spp. There are six families of efflux pumps that have been shown to be of clinical relevance: the Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR) family, ATP-binding cassette (ABC) family, Multidrug and Toxic Compound Extrusion (MATE) family, Proteobacterial Antimicrobial Compound Efflux (PACE) family and Resistance-Nodulation-Division (RND) family. A lot of work has been done on understanding and characterizing the roles that these efflux pumps play in relation to antimicrobial resistance and the physiology of these bacteria. RND efflux pumps, with their expansive substrate profiles, are a major component of Acinetobacter spp. antimicrobial resistance. New discoveries over the last decade have shed a lot of light on to the complex regulation of these efflux pumps leading to greater understanding and potential of slowing the reduced susceptibility seen by these bacterial species.

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Efflux-Mediated Antibiotic Resistance inAcinetobacterspp.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01388-10 ◽

2010 ◽

Vol 55 (3) ◽

pp. 947-953 ◽

Cited By ~ 256

Author(s):

Sébastien Coyne ◽

Patrice Courvalin ◽

Bruno Périchon

Keyword(s):

Multidrug Resistance ◽

Acquired Resistance ◽

Regulatory System ◽

Major Facilitator Superfamily ◽

Natural Resistance ◽

Major Mechanism ◽

Small Multidrug Resistance ◽

Genes Encoding ◽

Resistance Nodulation Division ◽

Major Facilitator

ABSTRACTAmongAcinetobacterspp.,A. baumanniiis the most frequently implicated in nosocomial infections, in particular in intensive care units. It was initially thought that multidrug resistance (MDR) in this species was due mainly to horizontal acquisition of resistance genes. However, it has recently become obvious that increased expression of chromosomal genes for efflux systems plays a major role in MDR. Among the five superfamilies of pumps, resistance-nodulation-division (RND) systems are the most prevalent in multiply resistantA. baumannii. RND pumps typically exhibit a wide substrate range that can include antibiotics, dyes, biocides, detergents, and antiseptics. Overexpression of AdeABC, secondary to mutations in theadeRSgenes encoding a two-component regulatory system, constitutes a major mechanism of multiresistance inA. baumannii. AdeIJK, intrinsic to this species, is responsible for natural resistance, but since overexpression above a certain threshold is toxic for the host, its contribution to acquired resistance is minimal. The recently described AdeFGH, probably regulated by a LysR-type transcriptional regulator, also confers multidrug resistance when overexpressed. Non-RND efflux systems, such as CraA, AmvA, AbeM, and AbeS, have also been characterized forA. baumannii, as have AdeXYZ and AdeDE for otherAcinetobacterspp. Finally, acquired narrow-spectrum efflux pumps, such as the major facilitator superfamily (MFS) members TetA, TetB, CmlA, and FloR and the small multidrug resistance (SMR) member QacE inAcinetobacterspp., have been detected and are mainly encoded by mobile genetic elements.

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Roles of Efflux Pumps from Different Superfamilies in the Surface-Associated Motility and Virulence of Acinetobacter baumannii ATCC 17978

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02190-18 ◽

2019 ◽

Vol 63 (3) ◽

Cited By ~ 3

Author(s):

María Pérez-Varela ◽

Jordi Corral ◽

Jesús Aranda ◽

Jordi Barbé

Keyword(s):

Acinetobacter Baumannii ◽

Efflux Pump ◽

Efflux Pumps ◽

Major Facilitator Superfamily ◽

Content Type ◽

Small Multidrug Resistance ◽

Genes Encoding ◽

Resistance Nodulation Division ◽

Major Facilitator ◽

Reported Data

ABSTRACT Although the relationship between Acinetobacter baumannii efflux pumps and antimicrobial resistance is well documented, less is known about the involvement of these proteins in the pathogenicity of this nosocomial pathogen. In previous work, we identified the AbaQ major facilitator superfamily (MFS) efflux pump and demonstrated its participation in the motility and virulence of A. baumannii. In the present study, we examined the role in these processes of A. baumannii transporters belonging to different superfamilies of efflux pumps. Genes encoding known or putative permeases belonging to efflux pump superfamilies other than the MFS were selected, and the corresponding knockouts were constructed. The antimicrobial susceptibilities of these mutants were consistent with previously reported data. In mutants of A. baumannii strain ATCC 17978 carrying inactivated genes encoding the efflux pumps A1S_2736 (resistance nodulation division [RND]), A1S_3371 (multidrug and toxic compound extrusion [MATE]), and A1S_0710 (small multidrug resistance [SMR]), as well as the newly described ATP-binding cassette (ABC) permeases A1S_1242 and A1S_2622, both surface-associated motility and virulence were reduced compared to the parental strain. However, inactivation of the genes encoding the known ABC permeases A1S_0536 and A1S_1535, the newly identified putative ABC permeases A1S_0027 and A1S_1057, or the proteobacterial antimicrobial compound efflux (PACE) transporters A1S_1503 and A1S_2063 had no effects on bacterial motility or virulence. Our results demonstrate the involvement of antimicrobial transporters belonging at least to five of the six known efflux pump superfamilies in both surface-associated motility and virulence in A. baumannii ATCC 17978.

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Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors

Pharmaceuticals ◽

10.3390/ph14060572 ◽

2021 ◽

Vol 14 (6) ◽

pp. 572

Author(s):

Fernando Durães ◽

Andreia Palmeira ◽

Bárbara Cruz ◽

Joana Freitas-Silva ◽

Nikoletta Szemerédi ◽

...

Keyword(s):

Quorum Sensing ◽

Mammalian Cells ◽

Efflux Pump ◽

Efflux Pumps ◽

Major Facilitator Superfamily ◽

Design And Synthesis ◽

Resistance Nodulation Division ◽

Efflux Pump Inhibitors ◽

Major Facilitator

The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation.

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Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

10.1101/2020.06.26.173484 ◽

2020 ◽

Author(s):

Yaojun Tong ◽

Nuo Sun ◽

Xiangming Wang ◽

Qi Wei ◽

Yu Zhang ◽

...

Keyword(s):

Candida Albicans ◽

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Multidrug Efflux Pump ◽

Drug Efflux Pumps ◽

Major Facilitator

AbstractClinical use of antimicrobials faces great challenges from the emergence of multidrug resistant (MDR) pathogens. The overexpression of drug efflux pumps is one of the major contributors to MDR. It is considered as a promising approach to overcome MDR by reversing the function of drug efflux pumps. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to multidrug resistance. Here we report a counterintuitive case of reversing multidrug resistance in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria, and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. It results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time (MST) of mice with a blood-borne dissemination of Mdr1p overexpressed multidrug resistant candidiasis. This study provided a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.

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Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06003-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2643-2651 ◽

Cited By ~ 87

Author(s):

Meenakshi Balganesh ◽

Neela Dinesh ◽

Sreevalli Sharma ◽

Sanjana Kuruppath ◽

Anju V. Nair ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Efflux Pump ◽

Efflux Pumps ◽

Vital Role ◽

Major Facilitator Superfamily ◽

Content Type ◽

Active Efflux ◽

Drug Candidates ◽

Small Multidrug Resistance ◽

Major Facilitator

ABSTRACTActive efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms inMycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil andl-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded byRv1218c, and the SMR (small multidrug resistance) class, encoded byRv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded byRv0849andRv1258calso mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WTM. tuberculosiscells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps ofM. tuberculosisplay a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization ofRv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

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Molecular Biology of Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily from Bacterial Food Pathogens

Foodborne Pathogens and Antibiotic Resistance ◽

10.1002/9781119139188.ch13 ◽

2017 ◽

pp. 303-329

Author(s):

K.C. Ranjana ◽

Ugina Shrestha ◽

Sanath Kumar ◽

Indrika Ranaweera ◽

Prathusha Kakarla ◽

...

Keyword(s):

Multidrug Resistance ◽

Molecular Biology ◽

Efflux Pumps ◽

Major Facilitator Superfamily ◽

Food Pathogens ◽

Major Facilitator ◽

Bacterial Food

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Membrane homoeostasis and multidrug resistance in yeast

Bioscience Reports ◽

10.1042/bsr20080071 ◽

2008 ◽

Vol 28 (4) ◽

pp. 217-228 ◽

Cited By ~ 17

Author(s):

Sneh Lata Panwar ◽

Ritu Pasrija ◽

Rajendra Prasad

Keyword(s):

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Membrane Lipid ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Proper Functioning ◽

Drug Efflux Pumps ◽

Drug Efflux Pump ◽

Major Facilitator

The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.

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Bifunctional Enzyme SpoT Is Involved in Biofilm Formation ofHelicobacter pyloriwith Multidrug Resistance by Upregulating Efflux Pump Hp1174 (gluP)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00957-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 9

Author(s):

Xiaoran Ge ◽

Yuying Cai ◽

Zhenghong Chen ◽

Sizhe Gao ◽

Xiwen Geng ◽

...

Keyword(s):

Multidrug Resistance ◽

Biofilm Formation ◽

Efflux Pump ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Major Facilitator Superfamily ◽

Bifunctional Enzyme ◽

Content Type ◽

H Pylori ◽

Major Facilitator

ABSTRACTThe drug resistance ofHelicobacter pyloriis gradually becoming a serious problem. Biofilm formation is an important factor that leads to multidrug resistance (MDR) in bacteria. The ability ofH. pylorito form biofilms on the gastric mucosa is known. However, there are few studies on the regulatory mechanisms ofH. pyloribiofilm formation and multidrug resistance. Guanosine 3′-diphosphate 5′-triphosphate and guanosine 3′,5′-bispyrophosphate [(p)ppGpp] are global regulatory factors and are synthesized inH. pyloriby the bifunctional enzyme SpoT. It has been reported that (p)ppGpp is involved in the biofilm formation and multidrug resistance of various bacteria. In this study, we found that SpoT also plays an important role inH. pyloribiofilm formation and multidrug resistance. Therefore, it was necessary to carry out some further studies regarding its regulatory mechanism. Considering that efflux pumps are of great importance in the biofilm formation and multidrug resistance of bacteria, we tried to determine whether efflux pumps controlled by SpoT participate in these activities. We found that Hp1174 (glucose/galactose transporter [gluP]), an efflux pump of the major facilitator superfamily (MFS), is highly expressed in biofilm-forming and multidrug-resistant (MDR)H. pyloristrains and is upregulated by SpoT. Through further research, we determined thatgluPis involved inH. pyloribiofilm formation and multidrug resistance. Furthermore, the average expression level ofgluPin the clinical MDR strains (C-MDR) was considerably higher than that in the clinical drug-sensitive strains (C-DSS). Taken together, our results revealed a novel molecular mechanism ofH. pyloriresistance to multidrug exposure.

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Antibiotic Susceptibility Profiles ofEscherichia coli Strains Lacking Multidrug Efflux Pump Genes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.4.1126-1136.2001 ◽

2001 ◽

Vol 45 (4) ◽

pp. 1126-1136 ◽

Cited By ~ 300

Author(s):

Mark C. Sulavik ◽

Chad Houseweart ◽

Christina Cramer ◽

Nilofer Jiwani ◽

Nicholas Murgolo ◽

...

Keyword(s):

Multidrug Resistance ◽

Efflux Pump ◽

Major Facilitator Superfamily ◽

Multidrug Efflux ◽

Intrinsic Resistance ◽

Multidrug Efflux Pump ◽

Gene Deletions ◽

Small Multidrug Resistance ◽

Major Facilitator ◽

Susceptibility Profiles

ABSTRACT The contribution of seven known and nine predicted genes or operons associated with multidrug resistance to the susceptibility of Escherichia coli W3110 was assessed for 20 different classes of antimicrobial compounds that include antibiotics, antiseptics, detergents, and dyes. Strains were constructed with deletions for genes in the major facilitator superfamily, the resistance nodulation-cell division family, the small multidrug resistance family, the ATP-binding cassette family, and outer membrane factors. The agar dilution MICs of 35 compounds were determined for strains with deletions for multidrug resistance (MDR) pumps. Deletions in acrAB or tolC resulted in increased susceptibilities to the majority of compounds tested. The remaining MDR pump gene deletions resulted in increased susceptibilities to far fewer compounds. The results identify which MDR pumps contribute to intrinsic resistance under the conditions tested and supply practical information useful for designing sensitive assay strains for cell-based screening of antibacterial compounds.

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