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

Author
item Cole, Marsha
item HOBDEN, JEFFERY - Louisiana State University Medical Center
item WARNER, ISIAH - Louisiana State University

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2015
Publication Date: 4/10/2015
Citation: Cole, M.R., Hobden, J.A., Warner, I.M. 2015. Recycling antibiotics into GUMBOS: A new combination strategy to combat multi-drug resistant bacteria. Molecules. (20):6466-6487.

Interpretive Summary: Multi-drug resistant (MDR) bacteria and the lack of new antibiotics in development have quickly evolved into a global crisis. New strategies utilizing existing previously approved drugs, outmoded antibiotics, or nonantibiotics with antibacterial properties are currently being explored to urgently restore the depleted arsenal of anti-infective agents. GUMBOS or groups of uniform materials based on organic salts offer a tailor-made strategy to treat MDR wound infections with fixed dose combinations and reduced toxicity. The combination of outmoded beta-lactam antibiotics and the toxic antiseptic chlorhexidine diacetate in the form of GUMBOS yielded profound antibacterial activity, synergy, and unique pharmacological profiles upon MDR bacteria that were significantly better than the conventional combination drug mixture. Thus, GUMBOS show promise as an alternative combination drug strategy for treating wound infections caused by drug resistant bacteria.

Technical Abstract: 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 ß-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. Antibacterial activity of precursor ions (e.g. chlorhexidine diacetate and ß-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 ß-lactam antibiotics and toxic chlorhexidine diacetate exhibited unique pharmacological properties and profound antibacterial activity at lower concentrations than the unreacted mixture of precursor ions at equivalent stoichiometry. GUMBOS were also less toxic to invasive cell types commonly found in superficial and chronic wounds. GUMBOS show promise as an alternative combination drug strategy for treating wound infections caused by drug resistant bacteria.