PMID- 25789871
OWN - NLM
STAT- MEDLINE
DCOM- 20160209
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 3
DP  - 2015
TI  - Membrane-active macromolecules resensitize NDM-1 gram-negative clinical isolates 
      to tetracycline antibiotics.
PG  - e0119422
LID - 10.1371/journal.pone.0119422 [doi]
LID - e0119422
AB  - 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.
FAU - Uppu, Divakara S S M
AU  - Uppu DS
AD  - Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal 
      Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 
      560064, India.
FAU - Manjunath, Goutham B
AU  - Manjunath GB
AD  - Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal 
      Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 
      560064, India.
FAU - Yarlagadda, Venkateswarlu
AU  - Yarlagadda V
AD  - Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal 
      Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 
      560064, India.
FAU - Kaviyil, Jyothi E
AU  - Kaviyil JE
AD  - Department of Neuromicrobiology, National Institute of Mental Health and Neuro 
      Sciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
FAU - Ravikumar, Raju
AU  - Ravikumar R
AD  - Department of Neuromicrobiology, National Institute of Mental Health and Neuro 
      Sciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
FAU - Paramanandham, Krishnamoorthy
AU  - Paramanandham K
AD  - National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), 
      Hebbal, Bengaluru, 560024, Karnataka, India.
FAU - Shome, Bibek R
AU  - Shome BR
AD  - National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), 
      Hebbal, Bengaluru, 560024, Karnataka, India.
FAU - Haldar, Jayanta
AU  - Haldar J
AD  - Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal 
      Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 
      560064, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150319
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Maleimides)
RN  - EC 3.5.2.6 (beta-Lactamases)
RN  - EC 3.5.2.6 (beta-lactamase NDM-1)
RN  - F8VB5M810T (Tetracycline)
SB  - IM
EIN - PLoS One. 2015;10(4):e0126757. PMID: 25879927
MH  - Animals
MH  - Cell Membrane/drug effects
MH  - Drug Resistance, Bacterial/drug effects
MH  - *Drug Synergism
MH  - Humans
MH  - Klebsiella Infections/*drug therapy/microbiology
MH  - Klebsiella pneumoniae/drug effects
MH  - Maleimides/*administration & dosage/chemistry
MH  - Membrane Potentials/drug effects
MH  - Mice
MH  - Tetracycline/*administration & dosage
MH  - beta-Lactamases/metabolism
PMC - PMC4366164
COIS- Competing Interests: Membrane-active molecules, discovered by DSSMU and JH, 
      described in the manuscript have been filed for a PCT application (WO 2014006601 
      A3). The authors' confirm that this does not alter their adherence to all the 
      PLOS ONE policies on sharing data and materials.
EDAT- 2015/03/20 06:00
MHDA- 2016/02/10 06:00
PMCR- 2015/03/19
CRDT- 2015/03/20 06:00
PHST- 2014/11/03 00:00 [received]
PHST- 2015/01/13 00:00 [accepted]
PHST- 2015/03/20 06:00 [entrez]
PHST- 2015/03/20 06:00 [pubmed]
PHST- 2016/02/10 06:00 [medline]
PHST- 2015/03/19 00:00 [pmc-release]
AID - PONE-D-14-43022 [pii]
AID - 10.1371/journal.pone.0119422 [doi]
PST - epublish
SO  - PLoS One. 2015 Mar 19;10(3):e0119422. doi: 10.1371/journal.pone.0119422. 
      eCollection 2015.