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

Abstract

Gram-negative ‘superbugs’ such as New Delhi metallo-beta-lactamase-1 (bla NDM-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 bla NDM-1 Klebsiella pneumonia and bla NDM-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 bla NDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs.

Membrane-active macromolecules kill antibiotic-tolerant bacteria and potentiate antibiotics towards Gram-negative bacteria

“…We found that the macromolecules restored the efficacy of existing antibiotics to as low as 0.1 μg mL -1 ( S2 and S3 Tables). Using the fractional inhibitory concentration (FIC = [X]/MIC X , where [X] is the lowest inhibitory concentration of compound 1 in the presence of the compound 2), a combination was called synergistic when the FIC index (FICI = FIC compound1 + FIC compound2 ) was ≤ 0.5 [ 34 ]. Both the molecules showed synergistic profiles with erythromycin and rifampicin against E .…”

“…baumannii (FICI in the range of 0.1–0.5) ( S2 Table ). Unlike erythromycin and rifampicin that are inherently resistant, Gram-negative bacteria acquire resistance to tetracycline antibiotics and we have recently reported that these cationic macromolecules resensitized planktonic cells of NDM-1 producing Gram-negative clinical isolates to tetracycline antibiotics [ 34 ]. These results suggested that this class of macromolecules have the potential to restore the efficacy of established antibiotics.…”

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

“…Macromolecules. Membrane-active macromolecules (MAMs) have been found to enhance the uptake of tetracycline by bacterial cells and therefore are able to resensitize NDM-positive strains to tetracycline (309). The MAM-tetracycline combination was bactericidal, in contrast to the bacteriostatic effect of tetracycline alone (309).…”

New Delhi Metallo-β-Lactamase-Mediated Carbapenem Resistance

“…However, colistin has uncertain efficacy in pulmonary infections, and its use has always been hampered by the occurrence of renal toxicity, and to a lesser extent, neurological adverse effects. [ 49 50 72 74 75 76 77 78 ] More importantly, carbapenem resistant bacteria such as blaNDM-1 E. coli and blaNDM-1 K. pneumoniae have become resistant to colistin. [ 77 ] Tigecycline is a glycylcycline with a wide spectrum of activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria.…”