AI Article Synopsis
- * A multitarget strategy is suggested, creating penicillin-based hybrids that inhibit CAs and resensitize drug-resistant bacteria to existing antibiotics.
- * Sulfonamide derivatives effectively inhibited CAs and showed strong effects against multidrug-resistant strains, outperforming traditional β-lactams and CA inhibitors.
Article Abstract
The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as , , and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from and with values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of indicated that these hybrid derivatives maintained the mechanism of action of the lead β-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant strains, with several compounds significantly outperforming both the lead β-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 μg/mL).
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| http://dx.doi.org/10.1021/acs.jmedchem.4c00740 | DOI Listing |
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