Sub lethal levels of platinum nanoparticle cures plasmid and in combination with carbapenem, curtails carbapenem resistant Escherichia coli

• Published in: Scientific reports 2019-03, Vol.9 (1), p.5305, Article 5305
• Main Authors: Bharathan, Subhashree, Sundaramoorthy, Niranjana Sri, Chandrasekaran, Harini, Rangappa, Gagana, ArunKumar, GaneshPrasad, Subramaniyan, Siva Bala, Veerappan, Anbazhagan, Nagarajan, Saisubramanian
• Format: Article
• Language: English
• Subjects: 14/28; 14/63; 42/44; 45/22; 45/77; 631/154/1435/2417; 631/326/107; 631/326/22/1434; 64/116; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Antimicrobial agents; Bacteria; Biofilms; Biofilms - drug effects; Ceftriaxone; Ceftriaxone - pharmacology; Ceftriaxone - therapeutic use; Cell Membrane - drug effects; Cell surface; Cell walls; Complementation; Curing; Danio rerio; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Cleavage - drug effects; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Drug Therapy, Combination; E coli; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - physiology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Gene transfer; Gene Transfer, Horizontal; Humanities and Social Sciences; Humans; Lethal levels; Meropenem; Meropenem - pharmacology; Meropenem - therapeutic use; Metal Nanoparticles - administration & dosage; Microbial Sensitivity Tests; Minimum inhibitory concentration; multidisciplinary; Nanoparticles; Pectin; Plasmids; Plasmids - drug effects; Plasmids - genetics; Platinum; Platinum - administration & dosage; Science; Science (multidisciplinary); Zebrafish; β Lactamase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41489-3

Drug resistance traits are rapidly disseminated across bacteria by horizontal gene transfer, especially through plasmids. Plasmid curing agents that are active both in vitro and in vivo will resensitize Multi Drug Resistant (MDR) bacteria to antimicrobial agents. Pectin capped platinum nanoparticles (PtNPs) at sub MIC (20 µM) concentration was effective, in causing loss of Extended Spectrum Beta Lactamase (ESBL) harboring plasmid as evidenced by, absence of plasmid in agarose gel and by a concomitant (16–64 fold) drop in MIC for cell wall inhibitors ceftriaxone and meropenem, in carbapenem resistant Escherichia coli (CREC). Interestingly, the plasmid cured strain exhibited small colony morphology and displayed slower growth both in vitro and in vivo . Complementation of cured strain with plasmid from the wild type strain restored resistance towards meropenem and ceftriaxone. Relative to wild type, plasmid cured strain displayed 50% reduction in biofilm formation. Plasmid curing also occurred in vivo in infected zebrafish with curing efficiency of 17% for nanoparticle + meropenem treatment. PtNPs + meropenem reduced bioburden of CREC in infected zebrafish by 2.4 log CFU. Mechanistic studies revealed that nanoparticle interacted with cell surface and perturbed inner membrane integrity. PtNPs did not induce ROS, yet it caused plasmid DNA cleavage, as evidenced by gyrase inhibition assay. Our study for the first time reveals that PtNPs as plasmid curing agent can resensitize MDR bacteria to selective antimicrobial agents in vivo .