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Title: Glycopeptide Antibiotic To Overcome the Intrinsic Resistance of Gram-Negative Bacteria
Authors: Yarlagadda, Venkateswarlu
Manjunath, Goutham B.
Sarkar, Paramita
Akkapeddi, Padma
Paramanandham, Krishnamoorthy
Shome, Bibek R.
Ravikumar, Raju
Haldar, Jayanta
Keywords: Pharmacology & Pharmacy
Infectious Diseases
intrinsic antibiotic resistance
Gram-negative bacteria
glycopeptide antibiotics
antibacterial activity
Cell-Wall Biosynthesis
Host-Defense Peptides
Issue Date: 2016
Publisher: American Chemical Society
Citation: Yarlagadda, V.; Manjunath, G. B.; Sarkar, P.; Akkapeddi, P.; Paramanandham, K.; Shome, B. R.; Ravikumar, R.; Haldar, J., Glycopeptide Antibiotic To Overcome the Intrinsic Resistance of Gram-Negative Bacteria. Acs Infectious Diseases 2016, 2 (2), 132-139
ACS Infectious Diseases
Abstract: The emergence of drug resistance along with a declining pipeline of clinically useful antibiotics has made it vital to develop more effective antimicrobial therapeutics, particularly against difficult-to-treat Gram-negative pathogens (GNPs). Many antibacterial agents, including glycopeptide antibiotics such as vancomycin, are inherently inactive toward GNPs because of their inability to cross the outer membrane of these pathogens. Here, we demonstrate, for the first time, lipophilic cationic (permanent positive charge) vancomycin analogues were able to permeabilize the outer membrane of GNPs and overcome the inherent resistance of GNPs toward glycopeptides. Unlike vancomycin, these analogues were shown to have a high activity against a variety of multidrug-resistant clinical isolates such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the murine model of carbapenem-resistant A. baumannii infection, the optimized compound showed potent activity with no observed toxicity. The notable activity of these compounds is attributed to the incorporation of new membrane disruption mechanisms (cytoplasmic membrane depolarization along with outer and inner (cytoplasmic) membrane permeabilization) into vancomycin. Therefore, our results indicate the potential of the present vancomycin analogues to be used against drug-resistant GNPs, thus strengthening the antibiotic arsenal for combating Gramnegative bacterial infections.
Description: Restricted Access
ISSN: 2373-8227
Appears in Collections:Research Papers (Jayanta Haldar)

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