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

Uppu DS, Manjunath GB, Yarlagadda V, Kaviyil JE, Ravikumar R, Paramanandham K, Shome BR, Haldar J - PLoS ONE (2015)

Bottom Line: Development of molecular strategies that can rehabilitate the 'old antibiotics' and halt the antibiotic resistance is a promising approach to target them.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.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.

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 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.

No MeSH data available.


Related in: MedlinePlus

(A) Structures of the membrane active molecules (MAMs) and (B) Schematic representation of agarose gel (2%) showing the 475 bp amplified product by conventional polymerase chain reaction.Lane 1, 100 bp DNA ladder; Lane 2, positive control- NDM-1 producing K. pneumoniae (ATCC-BAA-2146); Lane 3, negative control- E. coli (ATCC-25922); Lane 4, E. coli R3336 and Lane 5, K. pneumoniae R3934 confirm the blaNDM-1 gene; Lane 6, multi-drug resistant (MDR) K. pneumoniae R3421 which was negative for blaNDM-1 gene.
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pone.0119422.g001: (A) Structures of the membrane active molecules (MAMs) and (B) Schematic representation of agarose gel (2%) showing the 475 bp amplified product by conventional polymerase chain reaction.Lane 1, 100 bp DNA ladder; Lane 2, positive control- NDM-1 producing K. pneumoniae (ATCC-BAA-2146); Lane 3, negative control- E. coli (ATCC-25922); Lane 4, E. coli R3336 and Lane 5, K. pneumoniae R3934 confirm the blaNDM-1 gene; Lane 6, multi-drug resistant (MDR) K. pneumoniae R3421 which was negative for blaNDM-1 gene.

Mentions: One of the promising strategies to target multi-drug resistant (MDR) bacteria is by using either combination of two antibiotics or combination of antibiotics and non-antibiotics/adjuvants [5–16]. The combination of two or more antibiotics has been found to foster the development of bacterial resistance than the individual antibiotics [17]. An ideal combination approach would have at least one agent with lower rate of emergence of bacterial resistance. Molecules targeting the cell membrane of bacteria have been known to possess low propensity for triggering the development of bacterial resistance [18–24]. We have recently reported quaternized poly(isobutylene-alt-N-(N’,N’-dimethyl N’-alkyl aminopropyl)-maleimide) derivatives with membrane-active properties having excellent antibacterial efficacy against a panel of drug-resistant bacteria [23]. Thus, it would be ideal to entrust these polymeric derivatives, designated herein as membrane-active macromolecules (MAMs) (Fig. 1A), the role of re-sensitizing the superbugs to the antibiotics using a combination approach. In this report, we took an approach of developing molecular strategies to rehabilitate the ‘old antibiotics’ towards Gram-negative superbugs and attempted to support our observations using organismic studies and molecular reasoning, bridging both chemistry and biology. The mechanistic investigations of re-sensitization, membrane-active properties of MAMs and more importantly, the drug resistance studies of tetracycline antibiotics in presence of MAMs are reported herein.


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

Uppu DS, Manjunath GB, Yarlagadda V, Kaviyil JE, Ravikumar R, Paramanandham K, Shome BR, Haldar J - PLoS ONE (2015)

(A) Structures of the membrane active molecules (MAMs) and (B) Schematic representation of agarose gel (2%) showing the 475 bp amplified product by conventional polymerase chain reaction.Lane 1, 100 bp DNA ladder; Lane 2, positive control- NDM-1 producing K. pneumoniae (ATCC-BAA-2146); Lane 3, negative control- E. coli (ATCC-25922); Lane 4, E. coli R3336 and Lane 5, K. pneumoniae R3934 confirm the blaNDM-1 gene; Lane 6, multi-drug resistant (MDR) K. pneumoniae R3421 which was negative for blaNDM-1 gene.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4366164&req=5

pone.0119422.g001: (A) Structures of the membrane active molecules (MAMs) and (B) Schematic representation of agarose gel (2%) showing the 475 bp amplified product by conventional polymerase chain reaction.Lane 1, 100 bp DNA ladder; Lane 2, positive control- NDM-1 producing K. pneumoniae (ATCC-BAA-2146); Lane 3, negative control- E. coli (ATCC-25922); Lane 4, E. coli R3336 and Lane 5, K. pneumoniae R3934 confirm the blaNDM-1 gene; Lane 6, multi-drug resistant (MDR) K. pneumoniae R3421 which was negative for blaNDM-1 gene.
Mentions: One of the promising strategies to target multi-drug resistant (MDR) bacteria is by using either combination of two antibiotics or combination of antibiotics and non-antibiotics/adjuvants [5–16]. The combination of two or more antibiotics has been found to foster the development of bacterial resistance than the individual antibiotics [17]. An ideal combination approach would have at least one agent with lower rate of emergence of bacterial resistance. Molecules targeting the cell membrane of bacteria have been known to possess low propensity for triggering the development of bacterial resistance [18–24]. We have recently reported quaternized poly(isobutylene-alt-N-(N’,N’-dimethyl N’-alkyl aminopropyl)-maleimide) derivatives with membrane-active properties having excellent antibacterial efficacy against a panel of drug-resistant bacteria [23]. Thus, it would be ideal to entrust these polymeric derivatives, designated herein as membrane-active macromolecules (MAMs) (Fig. 1A), the role of re-sensitizing the superbugs to the antibiotics using a combination approach. In this report, we took an approach of developing molecular strategies to rehabilitate the ‘old antibiotics’ towards Gram-negative superbugs and attempted to support our observations using organismic studies and molecular reasoning, bridging both chemistry and biology. The mechanistic investigations of re-sensitization, membrane-active properties of MAMs and more importantly, the drug resistance studies of tetracycline antibiotics in presence of MAMs are reported herein.

Bottom Line: Development of molecular strategies that can rehabilitate the 'old antibiotics' and halt the antibiotic resistance is a promising approach to target them.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.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.

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 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.

No MeSH data available.


Related in: MedlinePlus