Title:Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery
Volume: 17
Issue: 19
Author(s): Renata Płocinska, Malgorzata Korycka-Machala, Przemyslaw Plocinski and Jaroslaw Dziadek*
Affiliation:
- The Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz,Poland
Keywords:
Tuberculosis, Multi drug resistance, Drug targets, DNA replication, Antimicrobial agent, RNA.
Abstract: Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis,
is a leading infectious disease organism, causing millions of deaths each year. This serious
pathogen has been greatly spread worldwide and recent years have observed an increase in the number
of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The
danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a
new generation of antimicrobial agents. The development of novel alternative medical strategies, new
drugs and the search for optimal drug targets are top priority areas of tuberculosis research.
Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically
silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired
drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging,
even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical
antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA
processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent
regulatory factors, lipid synthesis and the transition between the latent and actively growing
states.
Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis
therapy, describes putative drug targets evaluated in the recent literature and summarizes potential
candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA
replication, as a prominent target for future antituberculosis therapy. We describe two main pathways:
the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules.
We summarize data regarding replication associated proteins that are critical for nucleotide synthesis,
initiation, unwinding and elongation of the DNA during the replication process. They are pivotal
processes required for successful multiplication of the bacterial cells and hence they are extensively
investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors
of DNA synthesis and provide an up to date report on their status in the clinical trials.
