Membrane-active macromolecules resensitize NDM-1 gram-negative clinical isolates to tetracycline antibiotics

PloS One
Divakara S S M UppuJayanta Haldar

Abstract

Gram-negative 'superbugs' such as New Delhi metallo-beta-lactamase-1 (blaNDM-1) producing pathogens have become world's major public health threats. Development of molecular strategies that can rehabilitate the 'old antibiotics' and halt the antibiotic resistance is a promising approach to target them. We report membrane-active macromolecules (MAMs) that restore the antibacterial efficacy (enhancement by >80-1250 fold) of tetracycline antibiotics towards blaNDM-1 Klebsiella pneumonia and blaNDM-1 Escherichia coli clinical isolates. Organismic studies showed that bacteria had an increased and faster uptake of tetracycline in the presence of MAMs which is attributed to the mechanism of re-sensitization. Moreover, bacteria did not develop resistance to MAMs and MAMs stalled the development of bacterial resistance to tetracycline. MAMs displayed membrane-active properties such as dissipation of membrane potential and membrane-permeabilization that enabled higher uptake of tetracycline in bacteria. In-vivo toxicity studies displayed good safety profiles and preliminary in-vivo antibacterial efficacy studies showed that mice treated with MAMs in combination with antibiotics had significantly decreased bacterial burden compared to the...Continue Reading

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Citations

Sep 15, 2016·ACS Infectious Diseases·Venkateswarlu YarlagaddaJayanta Haldar
Sep 15, 2016·ACS Infectious Diseases·Chandradhish GhoshJayanta Haldar
Feb 4, 2016·Biomacromolecules·Divakara S S M Uppu, Jayanta Haldar
Feb 1, 2019·Clinical Microbiology Reviews·Wenjing WuZhiyong Zong
Sep 20, 2015·ChemMedChem·Chandradhish Ghosh, Jayanta Haldar
May 5, 2018·ACS Infectious Diseases·Venkateswarlu YarlagaddaJayanta Haldar

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Methods Mentioned

BETA
PCR
electrophoresis
Fluorescence
Assay

Software Mentioned

ARRIVE

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