Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

Abstract

Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR) as well as extensively drug-resistant (XDR) strains of M. tuberculosis, and the complications posed by co-infection with the human immunodeficiency virus (HIV) and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis. Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the development of drug resistance in M. tuberculosis, an organism which is unusual in relying exclusively on de novo mutations and chromosomal rearrangements for evolution, including the acquisition of drug resistance. In that context, we conclude by discussing the feasibility of targeting mutagenic pathways in an ancillary, “anti-evolution” strategy aimed at protecting existing and future TB drugs.

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

“…These second generation fluoroquinolones are safe, well tolerated, and have longer serum half‐life in the range of 4–10 h. In addition to these, newly synthesized 8‐methoxy fluoroquinolones, DC‐159a, is highly potent against drug susceptible, quinolone resistant bacteria and is currently in preclinical development stage . Furthermore, small molecules such as novobiocin, thiazolopyridine, benzofurans, thiazolopyridone ureas, and SPR‐720 have also been identified as inhibitors of GyrB subunit of DNA gyrase . In addition to DNA gyrase, other enzymes involved in DNA replication are also being explored as targets for anti‐tubercular agents .…”

“…Furthermore, small molecules such as novobiocin, thiazolopyridine, benzofurans, thiazolopyridone ureas, and SPR‐720 have also been identified as inhibitors of GyrB subunit of DNA gyrase . In addition to DNA gyrase, other enzymes involved in DNA replication are also being explored as targets for anti‐tubercular agents . For example, Kling et al, recently showed that DnaN, encoding β‐sliding clamp of M. tuberculosis , is the target for both methyl and cyclo‐hexyl derivatives of Griselimycin (SATB‐082) .…”

Structure of Thermococcus litoralis Δ1-pyrroline-2-carboxylate reductase in complex with NADH and L-proline

“…Hydroxyproline has been also proposed as a biomarker for tuberculosis (TB; Mach et al, 1973;Garcia-Zamalloa & Taboada-Gomez, 2012), the disease caused by Mycobacterium tuberculosis , since hydroxyproline is produced in TBassociated pulmonary fibrosis (Hernandez-Pando et al, 2004). Moreover, proline metabolism has been suggested as a promising target for the development of anti-infectives (Forlani et al, 2012), and the inhibition of this pathway could be taken into account for the development of potent anti-TB medicines, adding to the repertoire of (NADH-dependent) enzymes under consideration for the development of potent anti-TB medicines and adding to the repertoire of enzymes that have been considered as valid targets for the development of new antitubercular drugs, such as enzymes belonging to nucleotide-biosynthetic pathways (Paolino et al, 2018;Ferraris research papers et al, 2014Ferraris research papers et al, , 2015Sahu et al, 2018;Chacko et al, 2018;, to DNA-repair multi-step cascades and direct damage reversal pathways (Miggiano et al, 2016Morrone et al, 2017;Lahiri et al, 2018), and to DNA replication pathways (Reiche et al, 2017).…”

The Antibacterial Activity of a Fraction Extracted from Camel Urine against Mycobacterium tuberculosis Isolated from Tuberculosis Patients in Jeddah City

“…According to the most recent WHO report [8] the threat that TB presents to world health has been considerably heightened by the evolution and unfolding of drug-resistant TB: in 2015, a staggering 480,000 persons across the globe developed multi-drug resistant (MDR)-TB, outlined as TB that's proof against Rifampicin (RIF) and INH (INH), with or while not resistance to different first-line anti-tubercular medicine. Sadly, this example must continue to worsen victimization the XDR-TB to kinds of the un wellness that are functionally untreatable with existing antibiotics [15]. Camel urine has been consumed extensively for years in Saudi Arabia because it believed to be able to treat a large variety of diseases like cold, fever, or even cancer.…”