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Amino-Acid-Conjugated Polymer-Rifampicin Combination: Effective at Tackling Drug-Resistant Gram-Negative Clinical Isolates
journal contribution
posted on 2019-11-21, 17:04 authored by Swagatam Barman, Sudip Mukherjee, Sreyan Ghosh, Jayanta HaldarRapid 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.