The mechanistic basis of susceptibility and resistance to the antitubercular drug para-aminosalicylic acid
type: CreativeWork
description: Tuberculosis (TB) is responsible for the deaths of 1.6 million people worldwide each year and is the leading cause of death by the pathogen Mycobacterium tuberculosis. The treatment regimen for M. tuberculosis involves lengthy, intensive drug therapy that causes severe side-effects. The antimicrobial para-aminosalicylic acid (PAS) is used to treat drug-resistant M. tuberculosis infections. Despite the use of PAS to treat M. tuberculosis for over 70 years, the biochemical mechanisms which govern PAS susceptibility and resistance in M. tuberculosis are incomplete. The focus of this dissertation is to determine these mechanisms and can be summarized into three interrelated studies: 1) The mechanism of action of PAS on the M. tuberculosis folate metabolic pathway; 2) Understanding the mechanisms of PAS resistance; and 3) Examining the drug-drug interactions between PAS and other anti-folate drugs that are used to treat opportunistic infections in patients with HIV-M. tuberculosis co-infections. Chapter 2 shows that PAS is a pro-drug and is converted, via the M. tuberculosis folate biosynthetic pathway, to hydroxy-dihydrofolate. The folate biosynthesis pathway is an essential metabolic pathway used maintain the production of DNA, RNA, and proteins. Results showed that hydroxy-dihydrofolate acted as a potent inhibitor for dihydrofolate reductase and confirm the biochemical mode of action of PAS. Although PAS was originally found to be effective at inhibiting M. tuberculosis and showed no activity against other bacterial species. PAS activity was tested against other bacterial pathogens. While M. tuberculosis was extraordinarily sensitive to PAS, other bacteria resisted PAS-mediated killing. Chapter 2 found these bacterial species could utilize PAS as a fully functional folate analog into one-carbon metabolism. The folate biosynthesis precursor, para-aminobenzoic acid (PABA), is a known antagonist of antifolates, namely sulfonamides. Since PAS was shown to act similarly to…
abstract: Tuberculosis (TB) is responsible for the deaths of 1.6 million people worldwide each year and is the leading cause of death by the pathogen Mycobacterium tuberculosis. The treatment regimen for M. tuberculosis involves lengthy, intensive drug therapy that causes severe side-effects. The antimicrobial para-aminosalicylic acid (PAS) is used to treat drug-resistant M. tuberculosis infections. Despite the use of PAS to treat M. tuberculosis for over 70 years, the biochemical mechanisms which govern PAS susceptibility and resistance in M. tuberculosis are incomplete. The focus of this dissertation is to determine these mechanisms and can be summarized into three interrelated studies: 1) The mechanism of action of PAS on the M. tuberculosis folate metabolic pathway; 2) Understanding the mechanisms of PAS resistance; and 3) Examining the drug-drug interactions between PAS and other anti-folate drugs that are used to treat opportunistic infections in patients with HIV-M. tuberculosis co-infections. Chapter 2 shows that PAS is a pro-drug and is converted, via the M. tuberculosis folate biosynthetic pathway, to hydroxy-dihydrofolate. The folate biosynthesis pathway is an essential metabolic pathway used maintain the production of DNA, RNA, and proteins. Results showed that hydroxy-dihydrofolate acted as a potent inhibitor for dihydrofolate reductase and confirm the biochemical mode of action of PAS. Although PAS was originally found to be effective at inhibiting M. tuberculosis and showed no activity against other bacterial species. PAS activity was tested against other bacterial pathogens. While M. tuberculosis was extraordinarily sensitive to PAS, other bacteria resisted PAS-mediated killing. Chapter 2 found these bacterial species could utilize PAS as a fully functional folate analog into one-carbon metabolism. The folate biosynthesis precursor, para-aminobenzoic acid (PABA), is a known antagonist of antifolates, namely sulfonamides. Since PAS was shown to act similarly to…
author: Kordus, Shannon
language: en
keywords: antagonism, antifolates, folate biosynthesis, Mycobacterium tuberculosis, para-Aminosalicylic acid, Tuberculosis
date published: 2019-05
date modified: 2026-07-24T05:19:42Z
provider: University of Minnesota
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Minnesota

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property ID: Handle
value: http://hdl.handle.net/11299/206243