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 , which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against and . , the free amine of , exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant , the potent antibacterial efficacy of 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 as a potential antimicrobial agent for further research.