Multi‐functional small molecules with temporal charge‐switchability tackle infection and inflammation

Abstract

The alarming situation in public healthcare caused by ever-increasing catastrophe of antimicrobial resistance, recurrent infections, and associated inflammation has accelerated the hunt for novel therapeutics which can address these diverse problems concomitantly. This article introduces a new class of multi-functional amino acid conjugated small antibacterial molecules (ASAMs) which tackle complicated infections and associated inflammation. These molecules exhibit broad-spectrum bactericidal activity against multi-drug-resistant bacteria. The phenylalanine-bearing lead molecule (ASAM-10) tackles bacterial dormant subpopulations, impenetrable biofilms, and intracellular pathogens simultaneously. Importantly, this molecule addresses the problem of toxicity associated with cationic lipopeptides like colistin through the temporal charge switching (cationic to zwitterionic) owing to the degradation of labile ester linkages. However, this does not affect its desired antibacterial action window. The substantial reduction in the overexpression of pro-inflammatory cytokines (IL-6, IL-8, TNF-α, and IL-1β) upon treatment of infected macrophages with ASAM-10 validates its anti-inflammatory efficacy. Furthermore, bacteria exhibit diminished susceptibility toward resistance development against ASAM-10 owing to its membrane-active nature. ASAM-10 displays significant reduction in bacterial burden (2 Log CFU/g) when administered intraperitoneally in mice for MRSA thigh infection. Overall, this new class of multi-functional molecules is safe for anticipated advanced therapeutic applications to combat complex bacterial infections and inflammation.