Abstract
With prolonged therapy and increased instances of drug resistance, tuberculosis is viewed as a serious infectious disease causing high mortality. Emerging concepts in Mycobacterium tuberculosis pathogenicity include biofilm formation, which endows bacterial survival in the host for a long time. To tackle chronic tuberculosis infection, a detailed understanding of the bacterial survival mechanisms is crucial. Using comparative genomics and literature mining, 115 M. tuberculosis proteins were shortlisted for their likely association with biofilm formation or quorum sensing. These include essential genes such as secA2, lpqY-sugABC, Rv1176c, and Rv0195, many of which are also known virulence factors. Furthermore, the functional relationship among these proteins was established by considering known protein-protein interactions, regulatory interactions, and gene expression correlation data/information. Graph centrality and motif analyses predicted the importance of proteins, such as Rv0081, DevR, RegX3, Rv0097, and Rv1996 in M. tuberculosis biofilm formation. Analysis of conservation across other biofilm-forming bacteria suggests that most of these genes are conserved in mycobacteria. As the processes, such as quorum sensing, leading to biofilm formation involve diverse pathways and interactions between proteins, these system-wide studies provide a novel perspective toward understanding mycobacterial persistence.
Highlights
Tuberculosis claims millions of lives each year worldwide, thereby demanding immediate attention to discover efficient drug targets (Floyd et al, 2018)
Since other bacterial pathogens adopt the biofilm mode of growth during latent infection, a comparative genomics approach was utilized to test if genes implicated in biofilm formation and quorum sensing in other pathogenic bacteria were conserved in M. tuberculosis
Seven proteins with a LuxR domain and two proteins associated with c-di-GMP metabolism were considered, as they are likely to participate in downstream signaling during quorum sensing (Gupta et al, 2010; Chen and Xie, 2011; Fang et al, 2013)
Summary
Tuberculosis claims millions of lives each year worldwide, thereby demanding immediate attention to discover efficient drug targets (Floyd et al, 2018). The foremost challenge in tuberculosis treatment is the emergence of persisters (Höner and Russell, 2001; Stewart et al, 2003) This makes antibiotic treatment less effective as the persister population is typically drug-resistant. The persistence of most bacterial pathogens is facilitated by organized community structures called biofilms (HallStoodley and Stoodley, 2009) Mycobacterial species, such as M. marinum, M. fortuitum, and M. smegmatis, have been shown to form biofilms (Bardouniotis et al, 2003; Ojha et al, 2005; Ojha and Hatfull, 2007). In M. smegmatis, cells in the biofilms showed decreased susceptibility to isoniazid treatment compared to planktonic cultures (Teng and Dick, 2003).
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