Mycobacterium tuberculosis, the causative agent of tuberculosis, is a pathogen that affects more than one third of the world’s population. Its increasing resistance to antibiotics has made it particularly challenging for drug targeting efforts, as many of the drugs previously effective against the bacteria are no longer useful. New antibacterial agents are thus needed to combat infection. Acyldepepsipeptides (ADEPs), which cause unregulated protein degradation in bacteria, could prove to be a powerful new way to attack antibiotic resistant strains. These naturally occurring compounds are produced for chemical defense by Streptomyces hawaiians, and the Sello lab has synthesized a variety of ADEP analogs that target the clpP peptidase in Mycobacteria and Streptomyces. While it has been reported that these compounds are active against M. tuberculosis, ADEP export has also been detected: ADEP potency has been proven to increase when coadministered with compounds that inhibit efflux pumps, which are transmembrane transporters responsible for the export of antibiotics in drug-resistant bacteria. This pump has yet to be characterized. Because Streptomyces coelicolor--a relative of Mycobacteria--is non-pathogenic, easily genetically manipulated, and grows faster than M. tuberculosis, it is and ideal model organism for the exploration of which pump confers ADEP resistance in both Streptomyces and Mycobacteria. Bioinformatic analyses have implicated that an ABC-type transporter is involved in ADEP resistance. sco1719 and sco1720 are two genes in S. coelicolor that encode a promising ABC transporter candidate for the extrusion of ADEPs. sco1718 is hypothesized to encode its regulator, likely a repressor of the pump. These possibilities are explored through the creation of S. coelicolor strains lacking these genes and over expressing these genes.
Groomes, Patrice,
"Elucidating the mechanism of ADEP resistance in streptomyces coelicolor"
(2014).
Summer Research Symposium.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/4kn7-4h24
Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
