Antibiotics 2014, 3(1), 1-28; doi:10.3390/antibiotics3010001
Review

Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery

Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA Current address: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
Received: 1 November 2013; in revised form: 8 January 2014 / Accepted: 9 January 2014 / Published: 21 January 2014
(This article belongs to the Special Issue Feature Paper 2013)
PDF Full-text Download PDF Full-Text [1822 KB, Updated Version, uploaded 23 January 2014 16:13 CET]
The original version is still available [1888 KB, uploaded 21 January 2014 15:43 CET]
Abstract: The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such “off-target” effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for prokaryotic-specific polypharmacology for antimicrobial applications.
Keywords: folate pathway; antimicrobial; polypharmacology

Supplementary Files

Article Statistics

Load and display the download statistics.

Citations to this Article

Cite This Article

MDPI and ACS Style

Bourne, C.R. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery. Antibiotics 2014, 3, 1-28.

AMA Style

Bourne CR. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery. Antibiotics. 2014; 3(1):1-28.

Chicago/Turabian Style

Bourne, Christina R. 2014. "Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery." Antibiotics 3, no. 1: 1-28.

Antibiotics EISSN 2079-6382 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert