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Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B.

ABSTRACT: Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of Salmonella and at least two other Gram-negative bacteria in vitro This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.

SUBMITTER: Yadav J

PROVIDER: S-EPMC7674032 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B.

Yadav Jitender J Ismaeel Sana S Qadri Ayub A

Antimicrobial agents and chemotherapy 20201117 12

Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of <i>Salmonella</i> and at least two other Gram-negative bacteria <i>in vitro</i> This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination ma ...[more]

PMID: 32988824

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Project description:Antimicrobial resistance is a global public health threat. Antibiotic development pipeline has few new drugs; therefore, using antibiotic adjuvants has been envisioned as a successful method to preserve existing medications to fight multidrug-resistant (MDR) pathogens. In this study, we investigated the synergistic effect of a polymyxin derivative known as polymyxin B nonapeptide (PMBN) with azithromycin (AZT). A total of 54 Escherichia coli strains were first characterized for macrolide resistance genes, and susceptibility to different antibiotics, including AZT. A subset of 24 strains was then selected for synergy testing by the checkerboard assay. PMBN was able to re-sensitize the bacteria to AZT, even in strains with high minimum inhibitory concentrations (MIC: 32 to ≥128 μg/ml) for AZT, and in strains resistant to the last resort drugs such as colistin and meropenem. The fractional inhibitory concentration index was lower than 0.5, demonstrating that PMBN and AZT combinations had a synergistic effect. The combinations worked efficiently in strains carrying mphA gene encoding macrolide phosphotransferase which can cause macrolide inactivation. However, the combinations were inactive in strains having an additional ermB gene encoding macrolide methylase which causes ribosomal drug target alteration. Killing kinetics study showed a significant reduction of bacterial growth after 6 h of treatment with complete killing achieved after 24 h. Transmission electron microscopy showed morphological alterations in the bacteria treated with PMBN alone or in combination with AZT, with evidence of damage to the outer membrane. These results suggested that PMBN acted by increasing the permeability of bacterial outer membrane to AZT, which was also evident using a fluorometric assay. Using multiple antimicrobial agents could therefore be a promising strategy in the eradication of MDR bacteria. PMBN is a good candidate for use with other antibiotics to potentiate their activity, but further studies are required in vivo. This will significantly contribute to resolving antimicrobial resistance crisis.

Dataset Information

Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B.

Publications

Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B.

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