Mohammad Ashfaqul Alma Scope:COBRE in Pharmaceutical Research and Innovation

Grants and Contracts Details


This proposal’s objective is to elucidate the chemical biology of microbial metabolites and small molecules to specifically target intestinal pathogens, which cause intestinal infection & inflammation. The numerically vast and taxonomically diverse gut microbial communities affect the health and bacterial infection in the intestine. We and others have shown that the dysbiotic intestinal bloom of E. coli is strongly associated with exacerbated Campylobacter jejuni infection. C. jejuni is the primary pathogen responsible for bacterial gastrointestinal infections worldwide and is the leading cause of enteric inflammation in the United States, which can further lead to late-onset diseases such as Guillain Barré Syndrome, colorectal cancers, IBD, & IBS. Importantly, C. jejuni has been designated as a serious antibiotic resistance threat by both WHO & CDC and has become a significant concern for public health. However, there is a critical knowledge gap in developing potential anti-pathogen agents targeting only specific pathogens without disturbing the entire gut microbiota. Our exciting preliminary met’omics analysis identified increased abundances of E. coli’s amino acid decarboxylase system during C. jejuni infection in mice, which produces polyamines. Interestingly, the dysbiotic E. coli and its metabolites promoted C. jejuni’s infection by augmenting its chemotaxis, motility, survival in antibiotics, & toxin production. We also found that E. coli’s metabolites activate C. jejuni’s transducer-like proteins, and C. jejuni transducer-like protein mutants showed attenuated chemotaxis & virulence, indicating chemoreceptors as potential anti-virulent targets. CPRI Computational & Translational Core had virtually screened possible inhibitors of these bacterial virulence factors. We assayed and identified several potent blockers of polyamine metabolic pathways and chemosensing receptors. Our central hypothesis is that pathogens’ polyamine-producing enzymes & polyamine-sensing chemoreceptors are druggable targets to eliminate E. coli & C. jejuni by inhibiting chemotaxis, survival, & virulence during intestinal infection. In Aim 1, we will virtually screen small molecules which bind C. jejuni’s chemotactic receptor. In Aim 2, we will investigate the inhibitory impact and efficacy of top-ranked SPECS compounds on the chemotaxis of WT & mutants of C. jejuni by microplate-based assay and in vivo infection models. Finally, in Aim 3, we will assess the combined impact of inhibitors on C. jejuni-mediated infection in the mouse model. This project is both conceptually & technically innovative in developing the “anti-virulent agent” of C. jejuni & E. coli. In collaboration with COBRE CPRI core facilities, we assembled a strong investigative team. The findings will facilitate the development of intervention strategies to specifically control the emergence & spread of antibiotic resistance.
Effective start/end date3/1/201/31/24


  • National Institute of General Medical Sciences


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