Renee M Fleeman, Marc Giulianotti, Laura E Maida, Tina Yates-Gibbins, Angela Morales, Radleigh G Santos, Gregory S Welmaker, Richard A Houghten and Lindsey N Shaw
University of South Florida, USA
Posters & Accepted Abstracts: J Drug Metab Toxicol
Antibiotic resistance is a major global health issue for the 21st century due to an increasing number of bacterial species has become multi-drug resistance. Many species have become resistant to the majority or all of antibiotics available and extremely toxic drugs are being used to cure these infections because there is nothing left to treat them. The increase of antibiotic resistance combined with the decrease of FDA approval for novel therapeutics is driving us rapidly towards a post antibiotic era where antibiotics will be obsolete. If this lack of novel therapeutics continues, resistant antibiotic infections will be the leading cause of death by the year 2050. Mixture based synthetic combinatorial library screening offers a tremendous enhancement for the rate of drug discovery. This is due to the fact that the activity of millions of compounds can be accessed through the testing of exponentially fewer samples. To this end, we utilized the synthetic combinatorial screening to identify anti-resistance agents that cause multi-drug resistant species to be once again susceptible to clinical antibiotics that are no longer effective. From the initial screening we selected a triamine peptide library that decreased the effective concentration of tetracycline towards a clinical multi-drug resistant Pseudomonas aeruginosa by 4-fold without displaying any inhibitory effects alone. Deconvolution of this library was performed using the positional scanning approach to identify the functional groups at each variant position that created the greatest decrease in the effective concentration of tetracycline. Triamine lead agents were shown to decrease the tetracycline 90% effective concentration by an average 7.4-fold. In addition, these compounds displayed efflux inhibition of ethidium bromide of Gram negative and Gram positive organisms. The lead agents were not effective towards bacterial mutant strains lacking a major efflux pump revealing specificity towards efflux inhibition. These results demonstrate that employing synthetic combinatorial libraries to screen for anti-resistance agents can create a fundamental shift away from the traditional screening processes by introducing a rapid approach to discover novel agents that create susceptibility in multi-drug resistant species.
Email: rfleeman@mail.usf.edu
