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.
Highlights
The Need for New TB DrugsAccording to the most recent WHO report, 10.4 million people developed tuberculosis (TB) and 1.8 million died from this disease in 2015 (WHO, 2016), making TB the leading cause of death from an infectious disease
The threat that TB presents to global health has been significantly heightened by the evolution and spread of drug-resistant TB: in 2015, a staggering 480,000 people across the world developed multi-drug resistant (MDR)TB, defined as TB that is resistant to isoniazid (INH) and rifampicin (RIF), with or without resistance to other first-line anti-tubercular drugs
Though, there are signs indicating greater integration of the two approaches: on the one hand, target-based whole-cell screening, in which hit identification from phenotypic screening is biased toward prioritized targets and pathways, has begun to gain traction (Abrahams et al, 2012) while, on the other hand, screening collections of whole-cell actives identified by phenotypic approaches against high-value M. tuberculosis targets offers the prospect of discovering new drug-target pairs as starting points for hit-to-lead (H2L) programs (Esposito et al, 2017)
Summary
According to the most recent WHO report, 10.4 million people developed tuberculosis (TB) and 1.8 million died from this disease in 2015 (WHO, 2016), making TB the leading cause of death from an infectious disease. 9.5% had extensively drugresistant (XDR)-TB, which is resistant to INH and RIF (i.e., MDR-TB) in addition to any fluoroquinolone and at least one of the injectable second-line drugs, kanamycin, amikacin, or capreomycin This alarming situation has continued to worsen with the ongoing evolution of XDR-TB to forms of the disease that are functionally untreatable with existing antibiotics (Dheda et al, 2014). Drug-resistant TB is far more challenging to treat, requiring the administration of combinations of second- and third-line drugs that are more toxic, more expensive, and less efficacious As a result, this form of the disease is associated with substantial morbidity and mortality, while consuming a disproportionate share of national budgets for TB control in disease-endemic countries— compromising TB control programmes (Dheda et al, 2014, 2017). A major theme emerging from this work is the biological complexity of TB at the level of both host and pathogen, with the genotypic and phenotypic heterogeneity of M. tuberculosis posing onerous challenges for new TB drug discovery, as discussed below
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