Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

Coelho, Tatiane S.; Machado, Diana; Couto, Isabel; Maschmann, Raquel de Abreu; Ramos, Daniela Fernandes; Groll, Andréa von; Rossetti, Maria Lúcia Rosa; Silva, Pedro A.; Viveiros, Miguel

doi:10.3389/fmicb.2015.00330

Cited by 77 publications

(61 citation statements)

References 32 publications

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“…According to previous reports, the combination of an antibiotic and an efflux inhibitor at subminimal inhibitory concentrations delays the growth of M. tuberculosis drug-resistant strains (Coelho et al, 2015; Machado et al, 2017). Therefore, in R. anatipestifer drug-resistant strains, the EP is also believed to contribute to the overall level of antibiotic resistance described above.…”

Section: Resultsmentioning

confidence: 90%

“…Z. et al, 2016, chapter 28). The effects of some EPIs on antimicrobial susceptibilities have been studied in several microorganisms, including Escherichia coli (Opperman et al, 2014), Salmonella (Sutkuviene et al, 2013), Klebsiella pneumoniae (Chevalier et al, 2004), Mycobacterium tuberculosis (Coelho et al, 2015; Machado et al, 2017), Acinetobacter baumannii (Richmond et al, 2013), and Campylobacter (Kurincic et al, 2012). However, in regard to this, no systematic, comprehensive research has been conducted in R. anatipestifer .…”

Section: Introductionmentioning

confidence: 99%

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Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

et al. 2018

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The number of multidrug-resistant strains of Riemerella anatipestifer continues to increase, and new strategies for the treatment of associated infections are necessary. Recently, numerous studies have shown that efflux pumps (EPs) play key roles in universal bacterial mechanisms that contribute to antibiotic resistance. In addition, studies have shown that the effects of antibiotics that are subjected to efflux can be reinforced by their combined use with efflux pump inhibitors (EPIs). Unfortunately, the role of the efflux system in R. anatipestifer remains barely understood. In this study, we evaluated the role of EPs and resistance genes in the resistance generated by clinical strains of R. anatipestifer to antibiotics. A set of 10 R. anatipestifer strains were characterized by drug resistance, associated resistance genes, and antibiotic profiles in the presence and absence of EPIs. Efflux activity was studied on a real time basis through a fluorometric method. Quantification of the levels of mRNA transcription of efflux pump genes (EPGs) was determined by RT-qPCR. Several approaches (detection of resistance genes, drug susceptibility testing, and growth kinetics analysis) were used to assess the correlation between the effect of the EPIs and the resistance levels. Analysis of the R. anatipestifer growth inhibition tests showed that the antibiotic activity was enhanced by the synergy of EPIs. Among the various resistance genes that confer antibiotic resistance, different minimum inhibitory concentrations (MICs) were observed. The different levels of resistance were reduced by EPIs. Real time fluorometry showed that all the R. anatipestifer strains presented inherent efflux activity, conferring varying levels of inhibition in the presence of EPIs. Moreover, 15 EPGs were overexpressed in the presence of antibiotics. The addition of EPIs to antibiotics led to downregulation in the expression of some EPGs and a simultaneous increase in drug resistance and sensitivity. These results demonstrated the contribution of these EPs in the resistant phenotype of the clinical strains of R. anatipestifer that are under investigation, independently of the resistant genotype of the respective strains. Intrinsic efflux activity was possibly linked to the evolution of resistance in multidrug-resistant isolates of R. anatipestifer. Furthermore, the inhibition of EPs by EPIs could enhance the clinical effects of antibiotics.

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Section: Resultsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

et al. 2018

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“…220 In vitro studies show efflux inhibitors to be successful against AMK-resistant M. tuberculosis . 221 Other recent work includes a competitive, fluorescent dye assay for studying the efficacy of efflux pump inhibitors. 222 …”

Section: Efflux Pumpsmentioning

confidence: 99%

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

2016

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Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.

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“…The synergistic activity between the efflux inhibitors, antibiotics and EtBr was evaluated by checkerboard assays as previously described (Pillai, Moellering & Eliopoulos, 2005; Coelho et al, 2015). Two-fold serial dilutions of the compounds were made to achieve the following concentrations: 320 µM–40 µM.…”

Section: Methodsmentioning

confidence: 99%

Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli

Machado

Fernandes

Costa

et al. 2017

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Efflux pump inhibitors are of great interest since their use as adjuvants of bacterial chemotherapy can increase the intracellular concentrations of the antibiotics and assist in the battle against the rising of antibiotic-resistant bacteria. In this work, we have described the mode of action of the 2-phenylquinoline efflux inhibitor (4-(2-(piperazin-1-yl)ethoxy)-2-(4-propoxyphenyl) quinolone – PQQ4R), against Escherichia coli, by studding its efflux inhibitory ability, its synergistic activity in combination with antibiotics, and compared its effects with the inhibitors phenyl-arginine-β-naphthylamide (PAβN) and chlorpromazine (CPZ). The results showed that PQQ4R acts synergistically, in a concentration dependent manner, with antibiotics known to be subject to efflux in E. coli reducing their MIC in correlation with the inhibition of their efflux. Real-time fluorometry assays demonstrated that PQQ4R at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide inhibiting its efflux similarly to PAβN or CPZ, well-known and described efflux pump inhibitors for Gram-negative bacteria and whose clinical usage is limited by their levels of toxicity at clinical and bacteriological effective concentrations. The time-kill studies showed that PQQ4R, at bactericidal concentrations, has a rapid antimicrobial activity associated with a fast decrease of the intracellular ATP levels. The results also indicated that the mode of action of PQQ4R involves the destabilization of the E. coli inner membrane potential and ATP production impairment, ultimately leading to efflux pump inhibition by interference with the energy required by the efflux systems. At bactericidal concentrations, membrane permeabilization increases and finally ATP is totally depleted leading to cell death. Since drug resistance mediated by the activity of efflux pumps depends largely on the proton motive force (PMF), dissipaters of PMF such as PQQ4R, can be regarded as future adjuvants of conventional therapy against E. coli and other Gram-negative bacteria, especially their multidrug resistant forms. Their major limitation is the high toxicity for human cells at the concentrations needed to be effective against bacteria. Their future molecular optimization to improve the efflux inhibitory properties and reduce relative toxicity will optimize their potential for clinical usage against multi-drug resistant bacterial infections due to efflux.

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Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

Cited by 77 publications

References 32 publications

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli

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