Joe Matarlo

Graduate Student, Stony Brook University

Biochemistry and Structural Biology

Specialty: Chemical Biology and Drug Discovery: Microbiology and Enzymology

AGEP-T FRAME Research Mentor: Dr. Peter Tonge

Email: Matarlo.Joe@stonybrook.edu

I was born in the Philippines and immigrated into the USA when I was 10 years old. I am a proud graduate of St. Cecilia (Elementary), Bergen Catholic (HS), and Iona College from 1996 - 2009. At Iona, I discovered my passion for medical and scientific research. I held two distinct research projects during my undergraduate studies: Organic Chemistry and Neuro-Cellular Biology. Consequently, I worked as a research technician at Albert Einstein College of Medicine (Department of Hepatology) straight out of college until August 2011 after which I was admitted to the Biochemistry and Structural Biology program in Stony Brook.

Seminar Topic: "Mechanism of MenE Inhibition by Acyl-Adenylate Analogues: Discovery and Structure-Activity Relationships of Novel Antibacterial Agents"

Description: MenE, the o-succinylbenzoyl-CoA (OSB-CoA) synthetase in the bacterial menaquinone biosynthesis pathway, is a target for the development of novel antibacterial agents. The enzyme catalyzes CoA ligation via an acyl-adenylate, and previously we reported tight binding inhibitors of MenE based on stable acyl-adenylate analogues including OSB-AMS which has an IC50 value of ≤ 25 nM for the Escherichia coli MenE. In my current manuscript, we show that OSB-AMS reduces menaquinone levels in S. aureus, consistent with our proposed mode of action. To direct the synthesis of MenE inhibitors with improved antibacterial activity, we have undertaken an SAR study stimulated by the knowledge that OSB-AMS can exist in two isomeric forms in which the OSB group exists either as an open-chain keto acid or a cyclic lactol. Our current studies revealed that both isomers are able to inhibit MenE provided that the benzoic acid functionality bears a negative charge, consistent with the hypothesis that the negatively-charged keto-acid form of OSB-CoA is the active isomer. X-ray crystallography and site-directed mutagenesis confirm the importance of a conserved arginine for ligand binding, while the discovery of the difluoro-lactol MenE inhibitor points the way to the design of MenE inhibitors with improved antibacterial activity.