Recycling antibiotics into GUMBOS: a new combination strategy to combat multi-drug-resistant bacteria

• Published in: Molecules (Basel, Switzerland) Switzerland), 2015-04, Vol.20 (4), p.6466-6487
• Main Authors: Cole, Marsha R, Hobden, Jeffery A, Warner, Isiah M
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; antibacterial; Antibiotics; Antimicrobial agents; Bacteria; Bacteria - drug effects; beta-Lactams - chemistry; beta-Lactams - pharmacology; Cell Line; chlorhexidine; Chlorhexidine - chemistry; Chlorhexidine - pharmacology; combination drug therapy; Cytotoxicity; Drug dosages; Drug resistance; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Synergism; Drug therapy; Drug Therapy, Combination; GUMBOS; Humans; Infections; Inhibitory Concentration 50; Intestinal Absorption; ion pair; Mice; Microbial Sensitivity Tests; multi-drug resistant; Permeability; Pharmacokinetics; Salts - chemistry; Solubility; synergy; Toxicity; Wound healing; β-lactam antibiotic
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules20046466

The emergence of multi-drug-resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded β-lactam antibiotics (ampicillin, carbenicillin, cephalothin and oxacillin) and a well-known antiseptic (chlorhexidine di-acetate) were fashioned into a group of uniform materials based on organic salts (GUMBOS) as an alternative to conventional combination drug dosing strategies. The antibacterial activity of precursor ions (e.g., chlorhexidine diacetate and β-lactam antibiotics), GUMBOS and their unreacted mixtures were studied with 25 clinical isolates with varying antibiotic resistance using a micro-broth dilution method. Acute cytotoxicity and therapeutic indices were determined using fibroblasts, endothelial and cervical cell lines. Intestinal permeability was predicted using a parallel artificial membrane permeability assay. GUMBOS formed from ineffective β-lactam antibiotics and cytotoxic chlorhexidine diacetate exhibited unique pharmacological properties and profound antibacterial activity at lower concentrations than the unreacted mixture of precursor ions at equivalent stoichiometry. Reduced cytotoxicity to invasive cell types commonly found in superficial and chronic wounds was also observed using GUMBOS. GUMBOS show promise as an alternative combination drug strategy for treating wound infections caused by drug-resistant bacteria.