Keywords

Nitramines, Tuberculosis, Inhibition

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent behind tuberculosis, remains a significant global health issue, holding the position as the deadliest single-agent infection worldwide. Mtb relies on the glyoxylate shunt, a metabolic pathway, to promote its survival in low-oxygen and nutrient-scarce environments. Isocitrate lyase 1 (ICL1 EC 4.1.3.1) is the first major enzyme in this cycle, catalyzing the retro-aldol cleavage of d-isocitrate into succinate and glyoxylate. Furthermore, ICL1 has also been shown to play an important role in mediating antibiotic resistance towards common drugs used to treat tuberculosis, including streptomycin, isoniazid, and rifampicin. Neither the glyoxylate cycle nor ICL1 are present in mammals, making it a prime target for mycobacterial inhibition. Nitroalkanes, which share structural similarities to nitramines, are known inhibitors of ICL1, prompting investigation into the inhibitory potential of nitramines such as N-nitroglycine (NNG). This work focused on developing efficient methods for synthesizing nitramines to evaluate their potential as inhibitors of ICL1. The synthetic process involves the protection of the carboxyl groups of a Boc-protected substrate, followed by nitration and global deprotection of acid-labile protecting groups, with product purity confirmed by nuclear magnetic resonance (NMR) spectroscopy. Liquid chromatography-mass spectrometry (LC-MS) was used to determine if nitramines formed a covalent adduct with ICL1, and Ultraviolet-visible (UV-Vis) spectroscopy-based kinetics assays quantified the influence of nitramines on the rate of the ICL1 reaction. Our findings suggest a promising route of nitramine synthesis, allowing their investigation as inhibitors that have suggested they function differently than their nitroalkane counterparts in regard to ICL1 interaction.

Thesis Completion Year

2026

Thesis Completion Semester

Spring

Thesis Chair

Caranto, Jonathan

College

College of Sciences

Department

Chemistry

Thesis Discipline

Chemistry

Language

English

Access Status

Campus Access

Length of Campus Access

5 years

Campus Location

Orlando (Main) Campus

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Rights Statement

In Copyright