Membrane-Active Macromolecules Resensitize NDM-1 Gram-Negative Clinical Isolates to Tetracycline Antibiotics: e0119422

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 promis...

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Bibliographic Details
Published in:	PloS one Vol. 10; no. 3
Main Authors:	Uppu, S SM, Manjunath, Goutham B, Yarlagadda, Venkateswarlu, Kaviyil, Jyothi E, Ravikumar, Raju, Paramanandham, Krishnamoorthy, Shome, Bibek R, Haldar, Jayanta
Format:	Journal Article
Language:	English
Published:	01-03-2015
Subjects:	Escherichia coli Klebsiella
Online Access:	Get full text
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Summary:	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 untreated mice. This report of re-instating the efficacy of the antibiotics towards blaNDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2
ISSN:	1932-6203
DOI:	10.1371/journal.pone.0119422