The role of Mfd in Mycobacterium tuberculosis physiology and underlying regulatory network

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis with millions of deaths annually, remains one of the most formidable pathogen to global public health. As the most successful intracellular pathogens, Mtb can spatiotemporally coordinate the transcription and translation timely to reconcile the inevitable transcription-replication conflicts. Mutation frequency decline (Mfd) is a bacterial ATP-dependent DNA translocase that couples DNA repair to transcription via hydrolyzing ATP as energy, which preferentially acts on the damaged DNA transcribed strand to rescue stalled RNAP or dissociate RNAP to terminate the transcription depending on impediment severity, mitigating the damage to bacteria. In addition to the traditional damage repair effect, Mfd may also promote bacteria mutagenesis under stresses and boost the drug resistance. Mfd is widespread among bacteria and intensively studied, but there are very few studies in Mycobacteria, especially Mtb. In this review, the structure, function and mechanism characteristics of Mfd in Mtb (MtbMfd, Rv1020) are explored, with emphasis on the regulatory network of MtbMfd and its potential as a prime target for antibiotic drugs against tuberculosis.