Abstract
In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.
Highlights
Introductionmultidrug resistant (MDR) bacteria have caused already a few epidemics and this problem is increasing rapidly [5]
The routes for the synthesis of imidazolone (7–21) and thiazolone (22, 23) derivatives are depicted in Scheme 1, while the synthesis of compounds 7–10, 12–17, 19–21, 24–30, 32–38 has been described elsewhere [27,28]
Results for compounds 16 and 20 in ATCC 25923 strain were published previously [27]. These findings suggest that the compounds are not likely to become antibiotics by themselves, and are unlikely to elicit antibiotic resistance formation when added as an adjuvant molecule
Summary
MDR bacteria have caused already a few epidemics and this problem is increasing rapidly [5]. This issue has raised a lot of attention in recent years, all policies and incentives that have been proposed to combat MDR brought only a little progress yet, and the current lack of solutions is likely to exert major consequences on our healthcare system and may affect social and economic fields [6]. It is crucial to search for new antimicrobial drugs or other strategies able to overcome MDR [2,4,7,8] Such strategies include, for instance, the use of antibodies, bacteriophages, and antibiotic adjuvant therapy [9,10]. The great efficacy of chemosensitizers is related to inhibition of various mechanisms of bacterial resistance e.g., permeation across outer membrane, efflux pumps, modification of drug target, and enzymatic inactivation of drugs [8,10]
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