From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum towards Carbapenem-Resistant Bacteria.

Abstract

The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing the central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against MDR-Gram-positive clinical isolates, including vancomycin- and linezolid-resistant MRSA, with a minimum inhibitory concentration (MIC) value as low as 0.5 \uf06dg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2× the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 hours suggesting a once-daily dosing regimen.