Study of Environmental Pollutants' and Anti-Candida and Anti-beta-lactamase Drugs' Toxicities

摘要

b-lactams are a special class of antibiotics that block bacterial cell wall synthesis and play an important role as antibacterial medicines. However, bacteria have acquired resistance to b-lactams, in part through expression of b-lactamase enzyme which inactivatesb-lactam antibiotics. One objective of our studies was to screen a large panel of NMT compounds and identify b-lactamase inhibitors. Five structurally distinct compounds AKM 860, AKM270, AKM692, AKM228 & AKM9 were found to inhibit b-lactamase expressed off pUC18 plasmid in E. coli without showing any direct toxicity to either gram-negative or gram-positive cells at the same b-lactamase-inhibitory concentrations. Further analysis showed these compounds to be active at only very high concentrations, relegating them to the status of "leads" for potential subsequent studies.;The second part of this project was to evaluate certain pollutants for toxicity before and after degradation in the presence of environmentally-relevant clay and sun-light. Specifically, we focused on ibuprofen and clofibric acid which belong to the pharmaceutical and personal care products (PPCPs) pollutant category. The rapid V. fischeri bioluminescent assay was employed for this purpose and used to demonstrate that ibuprofen becomes less toxic while clofibric acid remains non-toxic after complete degradation under these conditions.;The third part of this project sought to identify novel drug leads against the wide-spread yeast pathogen Candida albicans whose eukaryotic nature makes drug selectivity over the human host cells particularly challenging. In this context we evaluated two families of novel compounds: polygodial analogues and IM antibacterials. Since the three best leads from these two series showed full killing only at concentrations which are toxic to cultured human cells, we attempted to improve their toxicity with compounds that might permeabilize Candida cell wall and synergize with these polygodial and IM leads. While anethole and chlorogenic acid did not enhance C. albicans killing, promising synergistic outcomes were discovered between poly-l-lysine in combination with all three of our polygodial and IM leads. Further work is needed to evaluate these drug combinations on Candida biofilms and hyphae, as well as for toxicity to human cells in culture.