Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria

G0775, an arylomycin-type SPase I
inhibitor that is being evaluated
in a preclinical study, exhibited potent antibacterial activities
against some Gram-negative bacteria but meanwhile suffered defects
such as a narrow antibacterial spectrum and poor pharmacokinetic properties.
Herein, systematic structural modifications were carried out, including
optimization of the macrocyclic skeleton, warheads, and lipophilic
regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against
clinically isolated carbapenem-resistant Gram-negative bacteria, especially
against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free
amine of 138f, exhibited an excellent pharmacokinetic
profile in rats. In a neutropenic mouse thigh model of infection with
multidrug-resistant P. aeruginosa,
the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease
vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.