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

Abstract

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

Moles of Molecules against Mycobacterium abscessus: A Review of Current Research

“…Three compounds showed IC50s ranging between 5.3-29.5 µM. Despite the 5-(2,4-bis(trifluoromethyl)phenyl) furan-2-carboxylic acid (compound 1, Table 9) assessed an IC50 of 5.3 ± 1.5 µM against the enzyme and decreased the production of the siderophore in a concentrationdependent manner, it did not show any toxic effect against Mab in liquid culture and ironlimiting condition up to 500 µM [128]. This preliminary data opens the path to new possibilities for the development of effective drugs against Mab.…”

“…For instance, targeting the biosynthesis of mycobacterial siderophores, known as mycobactins and involved in host iron scavenging, is an exquisite strategy attracting different study groups of Mtb. In Mab, the first enzyme involved in the mycobactins biosynthesis is the salicylate synthase SaS, which converts the chorismate into salicylate [128]. Since it is homologous in Mtb, the MbtI enzyme has been widely explored [129][130][131], and a library of putative inhibitors has been recently evaluated against Mab-SaS, considering the structural and functional similarities shared by these two proteins.…”

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

“…Similarly, an in silico virtual screening of a commercially available library led to the identification of a 5-phenylfuran-2-carboxylate compound, highly active against MbtI, and showing a moderate antitubercular activity in iron-depleted conditions, associated to a reduction in siderophore production [ 78 ]. Subsequent structure–activity relationship investigations were performed on this structure [ 79 , 80 , 81 , 82 , 83 ], leading to the identification of a series of 3-cyanophenyl derivatives with improved antimycobacterial properties. Most notably, some of them were also active against the homolog enzyme of the non-tuberculous opportunistic pathogen, M. abscessus ( Figure 6 H) [ 82 , 83 ].…”

“…Subsequent structure–activity relationship investigations were performed on this structure [ 79 , 80 , 81 , 82 , 83 ], leading to the identification of a series of 3-cyanophenyl derivatives with improved antimycobacterial properties. Most notably, some of them were also active against the homolog enzyme of the non-tuberculous opportunistic pathogen, M. abscessus ( Figure 6 H) [ 82 , 83 ].…”

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

“…For example, the timing of initiation and rate of RBC transfusions as well as the timing of splenectomy could have a direct effect on the rate of iron loading and the adoption of new chelation strategies [293,305]. Furthermore, the intervention of different pharmaceutical preparations and dietary molecules [306][307][308][309][310][311][312], and different diseases and their treatment [313][314][315][316][317][318][319], could also influence iron absorption and excretion, as well as modulation of regulatory molecules involved in iron metabolism and erythropoiesis and the effect of chelation therapy [278,279,[306][307][308][309][310][311][312][313][314][315][316][317][318][319][320][321].…”