Amino-Acid-Conjugated Polymer-Rifampicin Combination: Effective at Tackling Drug-Resistant Gram-Negative Clinical Isolates.

Abstract

Rapid emergence of multidrug-resistant Gram-negative pathogens coupled with their biofilm-forming capability have set a clinical ultimatum to global public health with an increasing rate of mortality. Recently, the World Health Organization (WHO) identified Acinetobacter baumannii, Pseudomonas aeruginosa, and enterobacteriaceae (Klebsiella pneumoniae, E. coli, etc.) as the pathogens of top priority because of their ability to cause difficult-to-treat life-threatening infections insusceptible to conventional antibiotic therapy. Hence, the severity of the current scenario necessitates the development of a potent therapeutic agent with a smart strategy. Toward this goal herein, we have explored the potency of membrane-active, amino-acid-conjugated polymers (ACPs) to combat notorious Gram-negative pathogens in combination with intrinsically resistant antibiotic rifampicin. The polymers were able to enhance the antibacterial potency of rifampicin against different drug-resistant Gram-negative bacteria by 4-66 fold. The combination, which consisted of glycine-conjugated polymer, ACP-1 (Gly), and rifampicin was rapidly bactericidal in nature. This combination also exhibited significant potency to disrupt the preformed biofilms of drug-resistant strains of P. aeruginosa and E. coli. More importantly, a negligible propensity of resistance development was observed against this combination, whereas a high level of resistance development was observed against the last-resort antibiotic, colistin. Furthermore, ACP-1 (Gly) displayed noticeably good 50% lethal dosage in different administration routes (LD50 (subcutaneous) > 179 mg/kg and LD50 (intraperitoneal) = 100 mg/kg) in a mouse model. Additionally, ACP-1 (Gly) did not show any adverse effect on mouse skin even at 200 mg/kg. Therefore, the results ensured that the ACP-1 (Gly) is suitable for both topical as well as systemic application. Altogether, the results indicated significant promises of the combination for further development as a therapeutic regimen to tackle the outbreak of critical Gram-negative bacteria.