Background: Buruli ulcer (BU), caused by Mycobacterium ulcerans is a neglected tropical disease characterized by necrotic skin lesions. Antibiotic therapy and excision of the lesions are the treatments for this chronic disease. During the management of the disease, the emergence of drug resistance in these bacilli is a major challenge. Therefore, there is a need to identify new drug targets against this important pathogen.
Objective: The study aimed to investigate novel drug targets exploring virulence factors of M. ulcerans by in silico analysis.
Methods: Virulence proteins encoded by the chromosome of Mycobacterium ulcerans strain Agy99 were retrieved and analyzed for their cellular localization, human non-homology and essentiality. Further, proteins were analyzed for their physio-chemical characterization, drug resistance analysis, protein interaction analysis, metabolic pathway prediction, and druggability prediction by various databases and online software to find their suitability as drug targets. The structure of the predicted drug targets was also modeled and validated. Among three predicted drug targets, MUL_4536 was subjected to molecular docking with some known inhibitor compounds also. Receptor-ligand complex with the highest binding energy was selected for molecular dynamic (MD) simulation to determine the structural stability of the complex.
Results: Three virulence proteins MUL_4536, MUL_3640, and MUL_2329 encoding enzymes iso-citrate lyase, lysine-N-oxygenase, pup-protein ligase, respectively were predicted as a drug target against M. ulcerans. Isocitrate lyase has been identified as a potential drug target in many other mycobacterial and non-mycobacterial diseases. Lysine-N-oxygenase is the enzyme of mycobactin biosynthesis pathway and pup-protein ligase is associated with the pup-proteasome system. Proteins of these pathways have been studied as attractive drug targets in previous research works, which further support our predictions.
Conclusion: Our computational analysis predicted new drug targets, which could be used to design drugs against M. ulcerans. However, these predicted proteins require further experimental validation for their potential use as drug targets.
[http://dx.doi.org/10.1371/journal.pmed.0020108] [PMID: 15839744]
[http://dx.doi.org/10.1016/S2214-109X(19)30171-8] [PMID: 31200890]
[http://dx.doi.org/10.3201/eid2512.190427] [PMID: 31742506]
[http://dx.doi.org/10.1016/S2214-109X(14)70223-2] [PMID: 25103396]
[http://dx.doi.org/10.1186/1471-2164-13-258] [PMID: 22712622]
[http://dx.doi.org/10.5694/mja13.11331] [PMID: 24641151]
[http://dx.doi.org/10.1128/JCM.03119-13] [PMID: 24478404]
[http://dx.doi.org/10.3390/pathogens9090747] [PMID: 32932580]
[http://dx.doi.org/10.3389/fcimb.2020.00109] [PMID: 32318354]
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[http://dx.doi.org/10.1021/acs.jcim.8b00963] [PMID: 30840452]
[http://dx.doi.org/10.1128/AAC.49.8.3182-3186.2005] [PMID: 16048922]
[http://dx.doi.org/10.1371/journal.pntd.0002739] [PMID: 24625583]
[http://dx.doi.org/10.1371/journal.pntd.0001473] [PMID: 22272368]
[http://dx.doi.org/10.1111/1346-8138.12851] [PMID: 25809502]
[http://dx.doi.org/10.1128/AAC.47.4.1228-1232.2003] [PMID: 12654651]
[http://dx.doi.org/10.2174/1386207323666200219120903] [PMID: 32072892]
[http://dx.doi.org/10.1371/journal.pone.0186401] [PMID: 29049350]
[http://dx.doi.org/10.3390/molecules23071550] [PMID: 29954088]
[http://dx.doi.org/10.1073/pnas.97.3.1252] [PMID: 10655517]
[http://dx.doi.org/10.1128/mBio.00122-17] [PMID: 28223451]
[http://dx.doi.org/10.15252/embj.201387076] [PMID: 24986881]