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

The
narrow antibacterial spectrum of phenylthiazole antibiotics was expanded
by replacing central thiazole with a pyrazole ring while maintaining
its other pharmacophoric features. The most promising derivative,
compound 23, was more potent than vancomycin against
multidrug-resistant Gram-positive clinical isolates, including vancomycin-
and linezolid-resistant methicillin-resistant Staphylococcus
aureus (MRSA), with a minimum inhibitory concentration
(MIC) value as low as 0.5 μg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic
carbapenem-resistant strains, such as Acinetobacter
baumannii, Klebsiella pneumoniae, and Escherichia 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 h, suggesting a once-daily
dosing regimen.