Triosephosphate Isomerase Inhibitors as Potential Drugs against Clostridium perfringens

Abstract

Clostridium perfringes is a gram‐positive anaerobic bacillus responsible for various infections in humans and the main cause of diseases such as gas gangrene, bacterial‐associated diarrhea and food poisoning. Resistances to conventional medications have been identified in different strains of C. perfringens. Therefore, the development of new drugs against this bacterium is necessary. Here we use structural information of C. perfringens (CpTIM) and human (HsTIM) triosephosphate isomerase to look for specific CpTIM inhibitors by means of high‐performance virtual detection. We selected nine compounds (C1 ‐ C9) with high probability of CpTIM binding and low potential to bind to HsTIM, these compounds without report of specific use as an antibiotic. We determined that C2 and C4 decrease the activity of CpTIM by approximately 60 %, while HsTIM is not primarily affected (10 %). Therefore, C2 and C4 or their chemical derivatives should be further investigated as potential drugs against Clostridium perfringens.

Potential Site to Direct Selective Compounds in the Triosephosphate Isomerase for the Development of New Drugs

“…It is determined that compound 2 and 4 , have a decrease in enzymatic activity of 25 and 50% respectively (Figure D).…”

Amoebicidal effect of 5,5′‐[(4‐nitrophenyl)methylene]bis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone), a new drug against Entamoeba histolytica

“…In this study, we used the D4 compound (Chembridge ID: 7141698), which has a specific use reported against TvTIM (D4 was selected by high‐throughput virtual screening‐directed amino acids not conserved in HsTIM), [ 28 ] as TIM is a therapeutic target currently used in other pharmacological developments against various pathogenic species, such as bacteria, parasites, and some types of cancer, [ 13,14,16,17,23,24,29 ] and D4 compound has not been reported as an amoebicide. [ 30 ]…”

“…7141698), which has a specific use reported against TvTIM (D4 was selected by high-throughput virtual screening-directed amino acids not conserved in HsTIM), [28] as TIM is a therapeutic target currently used in other pharmacological developments against various pathogenic species, such as bacteria, parasites, and some types of cancer, [13,14,16,17,23,24,29] and D4 compound has not been reported as an amoebicide. [30] We proposed that D4 is selective to EhTIM, as we used conformers of compound D4 for each TIM, and we described the main interaction in EhTIM and HsTIM, where we determined that "Site 1"…”

“…[ 8–12 ] Also, some works have proposed a selective target, such as the enzyme triosephosphate isomerase (TIM) [ 13 ] ; this glycolytic enzyme has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as Trypanosoma cruzi , Trypanosoma brucei , E. histolytica , Giardia duodenalis , Trichomonas vaginalis , Clostridium perfringens , among others. [ 14–24 ] In addition, other researchers are looking for the repositioning of commercial drugs as antiparasitics. [ 25,26 ] The triosephosphate isomerase of E. histolytica (EhTIM) [ 27 ] has an identity of 41.33% with human TIM (HsTIM); this difference in amino acids favors the development of new drugs with a selective target against EhTIM.…”

Esters of quinoxaline-7-carboxylate-1,4-di-N-oxide as Trichomonas vaginalis triosephosphate isomerase inhibitors

“…Recombinant TvTIM was obtained as previously described (27,28). The conversion of glyceraldehyde 3-phosphate (GAP) into dihydroxyacetone phosphate was followed to determine enzyme activity following a previous procedure (29)(30)(31)(32)(33)(34)(35).…”