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.

Biocide loaded shear-thinning hydrogel with anti-biofilm efficacy cures topical infection

“…S2 and S3 †). 33 Herein, the hydrogel formation was initially confirmed by vial inversion testing and a representative image for GGH-0.1 is shown in Fig. 1B.…”

“…Notably, this peptidomimetic molecule displayed admirable biofilm disruption ability, activity against intracellular pathogens, anti-inflammatory efficacy and bacteria were unable to develop spontaneous resistance against this compound. 33 Essentially, the rationale behind hydrogel formation is primarily the electrostatic interaction between the positively charged amine functionalities of gelatin and negatively charged acid functionalities of gellan. 42 Since the biocide bears positively charged quaternary amine moieties, it may interact electrostatically with the available negatively charged residues associated with the gellan counterpart.…”

“…Perturbation of the membrane potential and membrane permeability have been already been established to be one of the root factors in the antibacterial activity of ASAM-10 in our previous report. 33 Herein, the mechanism of action of the biocide-loaded hydrogel was further established using various microscopic and spectroscopic techniques.…”

“…4.10. Biofilm disruption assay 33,48 Crystal violet staining. The biofilm disruption efficacy was investigated against the established biofilms formed by MRSA R3545 and VRSA 4 clinical isolates.…”

“…Therefore, herein, a phenylalanine bearing peptidomimetic small antibacterial agent, ASAM-10 from our previous report, has been selected as a potential biocide for the engineering of a desired release-based hydrogel platform. 33 Therefore, in order to develop a material to tackle infection at wound sites with impaired vascularity, we impregnated ASAM-10 into a shear-thinning and injectable hydrogel matrix composed of gelatin and gellan. Injectable hydrogels with a shear-thinning nature are advantageous due to their ease of administration and moldability to wound beds.…”