The recalcitrance of pathogenic bacteria to antibiotic treatment has stimulated research into combination therapy of antimicrobial agents, or of antimicrobial agents in combination with antibiotic adjuvants. Synergistic action of the antimicrobials in combination can facilitate neutralization of the pathogens more effectively and rapidly than treatment with a single antibiotic. One particularly useful strategy entails pairing of an antimicrobial agent with other compounds designed to facilitate its delivery into bacteria. However, the delivery itself is often a daunting task as many pathogens are equipped with highly resilient outer membranes and, in the case of bacterial biofilms, are often further protected by an extensive layer of extracellular polysaccharides which limits the diffusion of the antimicrobial agents to the cells.<br/><br/>We have previously observed that inhibition of the bacterial isoprenoid pathway with fosmidomycin facilitates oxidative stress in the some species of bacteria, and it is known that fosmidomycin treatment can also result in a weakening of membrane stability in others. Unfortunately, the efficacy of fosmidomycin, an anionic phosphonate-based drug, is often hampered due to poor cellular uptake into planktonic cells. Similarly, some gallium salts have shown promise as antibiotic agents, but the low solubility of the gallium cation in aqueous environments can be a limitation to the bioavailability of these compounds. In this work, we have investigated the efficacy of anionic MEP pathway inhibitors and cationic gallium salts in combination with various antimicrobials and adjuvants, including ionic liquids. Ionic liquid formulations are observed to be particularly efficacious against bacterial biofilms as they are able to disrupt the protective extracellular polysaccharide layer in addition to solubilizing and delivering a wide range of chemically diverse antibiotics to the cells.

Ionic liquids as a matrix for delivery of chemically diverse antibiotics to bacterial biofilms

249th National Meeting (2015)

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