Molecular Libraries
Podium
Ashootosh Tripathi, PhD
Research Assistant Professor of Medicinal Chemistry
University of Michigan
If discovery of new antibiotics continues to vacillate while the ability of pathogenic microbes to develop resistance continues to surge, society’s medicine chest will soon lack effective treatments against a multitude of serious infections. To put the situation into context, over the last 30 years no new class of antibiotics has been introduced to mankind. Moreover, the majority of pharmaceutical efforts during the past six decades have focused on the synthetic enhancement of a limited set of unique core scaffolds. From these perspective, we envisioned that a more sustainable route to combat antibiotic resistance is the discovery of novel classes of antimicrobials, which would require a greatly improved antibiotic husbandry and a much effective list of unique microbial targets. Herein, we describe a robust high throughput antibacterial discovery platform involving key virulence and resistance mechanism as target against both gram-negative (A. baumannii, uropathogenic E. coli) and gram-positive (MRSA) pathogenic microbes.
In one of our recent effort, we envisioned to tackle one of the urgent challenge of UPEC which is the cause of recurrent UTIs in women. It has been previously demonstrated that UPEC iron acquisition systems are upregulated during infection. Therefore, we screened for molecules that inhibit the growth of UPEC in low iron media from a library of natural product extracts (NPEs) and identified a novel metabolite, nicoyamycins and performed effective dose dependent bioassay.
Acinetobacter baumannii has the ability to attach to a surface and build a complex matrix where they colonize to form a biofilm. To combat the widespread problem, we designed an in vitro screen to identify inhibitors of A. baumannii biofilms using NPEs derived from marine microbes. The strategy provided access to three novel metabolites, cahuitamycins with sub-micromolar efficacy. Efforts to assess starter unit diversification through their biosynthetic pathway lead to the production of unnatural analogues cahuitamycins D and E with increased potency.
Previously, we also envisaged that the targeted inhibition of siderophore staphyloferrin B of Staphylococcus aureus, holds considerable potential as a single or combined treatment for methicillin resistant S. aureus (MRSA). Therefore, we developed a biochemical assay against the non-ribosomal peptide synthetase independent siderophore (NIS) synthetase involved in biosynthetic pathway of staphyloferrin. Analysis of NPEs led to the isolation of a novel class of antibiotics, baulamycins, acting as reversible competitive inhibitors of SbnE enzyme.
The success of these studies provides a proof of concept towards the development of a new age discovery platform, providing solution for two major bottlenecks that impede the new drug pipeline: identification of novel drug leads and beating the resistance due to indirect microbial targeting without trying to kill the pathogen.