Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains

Spengler

International Journal of Antimicrobial Agents

et al. 2010

Enterobacter aerogenes predominates amongst Enterobacteriaceae species that are increasingly reported as producers of extended-spectrum beta-lactamases. Although this mechanism of resistance to beta-lactams is important, other mechanisms bestowing a multidrug-resistant (MDR) phenotype in this species are now well documented. Amongst these mechanisms is the overexpression of efflux pumps that extrude structurally unrelated antibiotics prior to their reaching their targets. Interestingly, although knowledge of the genetic background behind efflux pumps is rapidly advancing, few studies assess the physiological nature of the overall efflux pump system of this, or for that matter any other, bacterium. The study reported here evaluates physiologically the efflux pump system of an E. aerogenes ATCC reference as well as two strains whose MDR phenotypes are mediated by overexpressed efflux pumps. The activities of the efflux pumps in these strains are modulated by pH and glucose, although the effects of the latter are essentially restricted to pH 8, suggesting the presence of two general efflux pump systems, i.e. proton-motive force-dependent and ABC transporter types, respectively.

Section: Discussionmentioning

confidence: 88%

Physiological characterisation of the efflux pump system of antibiotic-susceptible and multidrug-resistant Enterobacter aerogenes

Spengler

International Journal of Antimicrobial Agents

et al. 2010

Expert Opinion on Drug Metabolism & Toxicology

“…EPIs activity is also notably dependent on the class of the antibiotic to which they are combined thus resulting in discrepancies between the activity level of antibiotic restored and the EPIs concentration used. This was examined in different comparative studies using quinoline/ quinazoline derivatives and PAβN as a standard [64,65,74,[84][85][86]. It was observed that they do not have the same chemosensitizing effect on ciprofloxacin, sparfloxacin, and erythromycin activity in E. aerogenes bacteria overexpressing AcrB efflux pump.…”

Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

Alibert

Diarra

Hernandez

et al. 2016

Self Cite

Introduction: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concen-tration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy. KEYWORDSEfflux pump; Gram-negative bacteria; antibiotic; multidrug resistance; inhibitor Article highlights• Efflux pumps play a major role in multidrug resistance in Gram-negative bacteria • The pharmacodynamic role of RND efflux pumps in antibiotic resis-tance opens up new perspectives to alternative therapeutics • Targeting efflux pumps consists in solving the problems of polyse-lectivity, drug accumulation, membrane permeability and pathogeni-city related to bacterial resistance mechanisms • How to validate efflux pumps as target for new combined therapy?• Efflux pump inhibitor could be used as adjuvant in antibiotic treatments

European Journal of Medicinal Chemistry

“…To study the possible synergistic activity, the potential inhibitors were added during incubation with nalidixic acid that has been well described as efflux pump substrate [3,6,7]. PAbN (MIC ¼ 5 mM on ATCC 13048 and CM-64 strains) was used as a reference EPI according to previous studies [23] at the concentration of 50 mM. The first generation of compounds 1e11 was tested in the concentration range 62.5e333 mM (Fig.…”

Section: Influence Of Hydantoins On Nalidixic Acid Micmentioning

confidence: 99%

Amine–alkyl derivatives of hydantoin: New tool to combat resistant bacteria

Handzlik

Szymańska

Chevalier

et al. 2011

Self Cite

a b s t r a c t A series of new 5,5-diphenylhydantoin derivatives with various amineealkyl terminal fragments at N1-position were synthesized. Then a series of twenty-eight compounds with the same hydantoin scaffold were evaluated for their potency to combat bacterial MultiDrug Resistance (MDR). Intrinsic antibacterial activities were first evaluated. As these compounds showed no direct activity on bacteria, their influence on minimal inhibitory concentration (MIC) of nalidixic acid was tested in two strains of Enterobacter aerogenes: the reference-strain ATCC-13048 and the CM-64 strain which over-produces AcrAB-TolC efflux pump. The compounds showed moderate-or low-anti-MDR properties. According to SAR-studies, hit compounds containing 2-methoxyphenylpiperazine at N1-terminal fragment and methylcarboxyl acid one at N3-position of hydantoin have been identified for further microbiological studies and pharmacomodulations to develop efflux pump inhibitors.