DNA Replication in Mycobacterium tuberculosis

The transfer of genetic material through successive generations is essential to the survival and evolution of all living organisms, including bacteria. As causative agent of tuberculosis (TB), Mycobacterium tuberculosis must complete successive cycles of transmission, infection, and disease in order to maintain a viable presence in the human population. And, like other pathogens ( 1 ), M. tuberculosis is faced with the extra problem of regulating DNA replication, chromosomal segregation, and cell division while residing in diverse anatomical and cellular loci within its human host—including extra- and intracellular compartments ( 2 , 3 ). Therefore, in addition to the metabolic challenges faced during infection of dynamic and often hostile environments ( 4 , 5 ), M. tuberculosis is likely to encounter multiple stresses that are directly or indirectly genotoxic ( 6 – 8 ). In patients with active TB disease, these stresses might arise from host-derived antimicrobial immune effectors, generation of toxic by-products from host and/or mycobacterial metabolism, changes in intracellular redox potential as a function of shifts in metabolic activity, pH, or oxygen availability, or even exposure to anti-TB drugs. However, given that the number of active TB cases (although devastatingly high in absolute terms) is small relative to the total number of estimated infections ( 9 ), an additional feature of M. tuberculosis is the ability of infecting bacilli to persist for decades in a poorly understood subclinical state ( 10 , 11 ), in some cases reactivating decades later to cause postprimary TB ( 12 , 13 ). Under these conditions, DNA replication and repair pathways are predicted to be essential for preserving the genetic content and viability of bacilli located in lesions characterized by different states of immune activation at various stages throughout the disease cycle ( 14 ).