【For INTERNATIONAL COLLABORATIVE RESEARCH 2022】

SUMMARY of

DATE: Day 12Month 05

Year 2023

2022 RESEARCH RESULTS REPORTFor International Collaborative Research with IPR, Osaka University
Research Title

Drug screen strategy targeting RpoS against bacterial antibiotic
resistance

Applicant

Name

SAQIB UZMA

Affiliation

Indian Institute of Technology Indore

Present Title

Woman Scientist

Research Collaborator (Host PI)

Kenji Mizuguchi

Summary

The role of RpoS in protecting bacteria against antibiotics as well as their constitutive expression in bacterial
cells minimize the antibiotic sensitivity in a multidrug-resistant strain of E. coli. Hence, newer therapeuticstrategies should be employed to inhibit this bacterial defense protein. In the proposed work, we planned toscreen novel compounds from multiple public databases in pursuit of potent inhibitory molecules against
RpoS. This will be followed by testing the candidate compound(s) for their efficacy to weaken the UPEC
resistance to gentamicin. Gentamicin belongs to a class of drugs known as aminoglycoside antibiotics.
Gentamicin is used to treat several types of bacterial infections including bone infections, inflammatory
diseases, meningitis, pneumonia, urinary tract infections (UTI’s), and sepsis among others. We anticipate that
our ongoing work will discover novel candidates effective in inhibiting RpoS and eventually antibioticresistance. Also, this will be the first-of-its-kind study on RpoS based inhibitor discovery against UPEC.
Specific aims:
We proposed the following objectives;
Aim1: To identify novel RpoS inhibitors using in silico database search.
Aim2: To determine the potency of selected compounds in inhibiting RpoS in UPEC.
The goal of Aim1 was to develop potent RpoS inhibitory compounds using structure-based computationalscreening. We utilized a high resolution crystal structure of Rpos (PDB 5IPL) to screen compounds fromvarious databases, including; ZINC, Maybridge and microbial database. Our high-throughput virtual screen
strategy involved docking based analysis. Hence, we used state-of-the-art docking software programs basedon AutoDock to sequentially dock the datasets. This was preceded by identifying the binding site of theenzyme for potential inhibitors. Inclusion of compounds from multiple datasets would be beneficial in getting
molecules of different scaffolds, which in turn increases diversity and potency. After a thorough investigationof “hits” from the molecular docking run using scoring methods and binding site analysis, we moved to ourAim 2. Currently, we are performing experiments to test the efficacy of the compounds using reactive oxygen
species (ROS) assay.
We anticipate that targeting RpoS with screened compounds would increase the ROS formation inside thebacterial cell further disrupting the structural configuration of the gut microbiota. By selectively depleting
intestinal UPEC reservoirs, the selected compounds could be anticipated to reduce the rate of Urinary
Tract Infections (UTIs).

【For INTERNATIONAL COLLABORATIVE RESEARCH 2022】*Deadline: May 12, 2023
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