Approaches for targeting the mycobactin biosynthesis pathway for novel anti-tubercular drug discovery: where we stand

Unlocking Opportunities for Mycobacterium leprae and Mycobacterium ulcerans

“…Like other mycobacteria, M. ulcerans and M. leprae require iron for growth, while high extracellular iron levels could cause irreparable oxidative damage. , Iron acts as an enzyme cofactor in several essential biological processes (respiration, DNA synthesis, and protection from reactive oxygen species), and due to this essentiality, the host also restricts access to iron as an antimicrobial mechanism. In the iron-limiting macrophage milieu, mycobacteria have evolved a specific iron-scavenging mechanism to acquire iron from the host environment.…”

“…In the iron-limiting macrophage milieu, mycobacteria have evolved a specific iron-scavenging mechanism to acquire iron from the host environment. Particularly in iron-stress conditions, mycobacteria secrete conditionally essential iron scavengers: siderophores. , Researchers have highlighted that other than siderophore expression genes (inversely related to IdeR activation), while non-IdeR-dependent proteins involved in iron metabolism are overproduced, such as Mul_3902 (encoded IrtA), siderophore transporters Mul_1209 and Mul_1210, respectively, encoding EsxG and ESsxH, and MmpLS5 and MmpL5 export genes are also overexpressed in 7.5% glucose-enriched medium. They reported that the export machines of mycolactone and mycobactin act as scaffolds for their respective biosynthetic machines, although coupled elongation and export machines are not very uncommon in mycobacteria (it has been noted in the regulation of phthiocerol dimycocerosates and glycopeptidolipids in mycobacteria as well). , In correlation, it was hypothesized that mycolactone and mycobactin and their respective biosynthetic complexes compete for the same translocation machinery, which may explain the disappearance of mycolactone when mycobactin production is induced.…”

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays

“…In the context of novel EPI discovery, we would like highlight RND efflux-pump mediated siderophore recycling and iron-homeostasis mechanism in mycobacteria commonly shared by pathogenic-Mtb and opportunistic-NTMs (Shyam et al, 2021;Shyam et al, 2022a). Iron is an essential micronutrient that mycobacteria require for their colonization and growth; however, free iron is highly restricted in host environments (approximately 10 −24 M in human serum and body fluids).…”

“…During infection in the host macrophages, mycobacteria produce salicyl-capped siderophores to chelate and internalize iron from the host ironbinding proteins to support their biomachinery. In particular, a hydrophilic siderophore, termed carboxymycobactin (cMBT), is released into the extracellular environment to chelate Fe 3+ to form the Fe-cMBT complex (Figure 1) (Shyam et al, 2021;Shyam et al, 2022a). The Fe-cMBT complex is transported into the periplasmic space to release free iron.…”

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

“…In this regard, it has been shown that mutations in the enzymes involved in this process can lead to lower growth of Mtb in macrophages and decreased virulence in mice [ 10 , 11 ]. The possibility of effectively targeting these enzymes with small-molecule inhibitors has been demonstrated in many studies [ 12 , 13 ]. The Salicylate Synthase (SaS) from Mtb (MbtI) is the first enzyme involved in siderophore production; it catalyzes the two-step conversion of chorismate to salicylate, via isochorismate as an intermediate, acting as both an isomerase and a lyase ( Figure 1 ).…”