Author:
Tha Suprim,Shakya Sapana,Malla Rajani,Aryal Pramod
Abstract
Abstract
Background
It is prudent that novel classes of antibiotics be urgently developed to manage the WHO prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis. Simultaneously, multiple essential proteins have to be targeted to prevent easy resistance development.
Methods
An integration of structure-based virtual screening and ligand-based virtual screening was employed to explore the antimicrobial properties of indole derivatives from a compound database.
Results
Whole-genome sequences of the target pathogens were aligned exploiting DNA alignment potential of MAUVE to identify putative common lead target proteins. S-adenosyl methionine (SAM) biosynthesizing MetK was taken as the lead target and various literature searches revealed that SAM is a critical metabolite. Furthermore, SAM utilizing CobA involved in the B12 biosynthesis pathway, Dam in the regulation of replication and protein expression, and TrmD in methylation of tRNA were also taken as drug targets. The ligand library of 715 indole derivatives chosen based on kinase inhibition potential of indoles was created from which 102 were pursued based on ADME/T scores. Among these, 5 potential inhibitors of MetK in N. gonorrhoeae were further expanded to molecular docking studies in MetK proteins of all nine pathogens among which 3 derivatives exhibited inhibition potential. These 3 upon docking in other SAM utilizing enzymes, CobA, Dam, and TrmD gave 2 potential compounds with multiple targets. Further, docking with human MetK homolog also showed probable inhibitory effects however SAM requirements can be replenished from external sources since SAM transporters are present in humans.
Conclusions
We believe these molecules 3-[(4-hydroxyphenyl)methyl]-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione (ZINC04899565) and 1-[(3S)-3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-1-yl]ethanone (ZINC49171024) could be a starting point to help develop broad-spectrum antibiotics against infections caused by N. gonorrhoeae, A. baumannii, C. coli, K. pneumoniae, E. faecium, H. pylori, P. aeruginosa, S. aureus and S. typhi.
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Pharmacology
Reference52 articles.
1. Tello A, Austin B, Telfer TC. Selective pressure of antibiotic pollution on bacteria of importance to public health. Environ Health Perspect. 2012;120(8):1100–6. https://doi.org/10.1289/ehp.1104650.
2. Caniaux I, van Belkum A, Zambardi G, Poirel L, Gros MF. MCR: modern colistin resistance. Eur J Clin Microbiol Infect Dis, 2017;36:415–420. https://doi.org/10.1007/s10096-016-2846-y.
3. University, T. Tufts CSDD assessment of cost to develop and win marketing approval for a new drug now published. In: Retrieved from development. Tufts: Center for the Study of Drug website; 2016. http://csdd.tufts.edu/news/complete_story/tufts_csdd_rd_cost_study_now_published.
4. Sliwoski G, Kothiwale S, Meiler J, Lowe EW. Computational methods in drug discovery. Pharmacol Rev. 2014;66(1):334–95. https://doi.org/10.1124/pr.112.007336.
5. Lawe-Davies O, Bennett S. WHO publishes list of bacteria for which new antibiotics are urgently needed: WHO; 2017. p. 1. Retrieved from http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/.
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献