Investigating the role of l-asparaginase as a potential therapeutic target against gonorrhea infections

Vashishtha, Shubham; Kundu, Bishwajit

doi:10.1016/j.bpj.2021.11.1787

Cited by 2 publications

(5 citation statements)

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“…FDA‐approved drugs Pemirolast and thalidomide appeared among the top hits. Interestingly, the same drugs were reported earlier by us as potent N. gonorrhoeae L‐asparaginase (NgA) inhibitors 30,31 . Interestingly, the data from our previous study highlights complete growth inhibition with pemirolast and thalidomide.…”

Section: Discussionsupporting

confidence: 80%

“…Interestingly, the same drugs were reported earlier by us as potent N. gonorrhoeae L-asparaginase (NgA) inhibitors. 30,31 Interestingly, the data from our previous study highlights complete growth inhibition with pemirolast and thalidomide. However, the action of another drug decitabine, which specifically targets only Lasparaginase, showed comparatively less inhibition.…”

Section: Discussionmentioning

confidence: 84%

“…Interestingly, the data from our previous study highlights complete growth inhibition with pemirolast and thalidomide. However, the action of another drug decitabine, which specifically targets only L‐asparaginase, showed comparatively less inhibition 30,31 . This underlines that the inhibitory potency of the former two drugs is possibly due to their action against dual targets (NgHtpX and NgA).…”

Section: Discussionmentioning

confidence: 94%

“…However, the action of another drug decitabine, which specifically targets only Lasparaginase, showed comparatively less inhibition. 30,31 This underlines that the inhibitory potency of the former two drugs is possibly due to their action against dual targets (NgHtpX and NgA). We found strong binding interaction of the drugs with the HEXXH motif, which might compromise the Zn 2+ -binding function of NgHtpX, thereby inhibiting its autocatalytic activity.…”

Section: Discussionmentioning

confidence: 94%

“…We have earlier shown these two drugs to inhibit the activity of N. gonorrhoeae L-asparaginase (NgA). 30,31 Our study concludes that NgHtpX can be a mainline or adjunct molecular target, and selected drugs against it may act as potential therapeutics to control AMR gonorrhoea infections.…”

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confidence: 83%

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Evolutionarily conserved heat shock protein, HtpX, as an adjunct target against antibiotic‐resistant Neisseria gonorrhoeae

Vashishtha,

Thakur,

Singh

et al. 2023

J of Cellular Biochemistry

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The emergence of multiple drug resistance and extreme drug resistance pathogens necessitates the continuous evaluation of the pathogenic genome to identify conserved molecular targets and their respective inhibitors. In this study, we mapped the global mutational landscape of Neisseria gonorrhoeae (an intracellular pathogen notoriously known to cause the sexually transmitted disease gonorrhoea). We identified highly variable amino acid positions in the antibiotic target genes like the penA, ponA, 23s rRNA, rpoB, gyrA, parC, mtrR and porB. Some variations are directly reported to confer resistance to the currently used front‐line drugs like ceftriaxone, cefixime, azithromycin and ciprofloxacin. Further, by whole genome comparison and Shannon entropy analysis, we identified a completely conserved protein HtpX in the drug‐resistant as well as susceptible isolates of N. gonorrhoeae (NgHtpX). Comparison with the only available information of Escherichia coli HtpX suggested it to be a transmembrane metalloprotease having a role in stress response. The critical zinc‐binding residue of NgHtpX was mapped to E141. By applying composite high throughput screening followed by MD simulations, we identified pemirolast and thalidomide as high‐energy binding ligands of NgHtpX. Following cloning and expression of the purified metal‐binding domain of NgHtpX (NgHtpXd), its Zn2+‐binding (Kd = 0.4 µM) and drug‐binding (pemirolast, Kd = 3.47 µM; and thalidomide, Kd = 1.04 µM) potentials were determined using in‐vitro fluorescence quenching experiment. When tested on N. gonorrhoeae cultures, both the ligands imposed a dose‐dependent reduction in viability. Overall, our results provide high entropy positions in the targets of presently used antibiotics, which can be further explored to understand the AMR mechanism. Additionally, HtpX and its specific inhibitors identified can be utilised effectively in managing gonococcal infections.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 83%

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