Advances in Mycobacterial Isocitrate Lyase Targeting and Inhibitors

Abstract

Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 ± 0.01 μM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate.

Inhibitors of the Glyoxylate Cycle Enzyme ICL1 in Candida albicans for Potential Use as Antifungal Agents

“…Recently, ICL was found to be essential for virulence of several other pathogens, and it has been explored as a potential drug target in some of them [18], [19], [20], [21], [22]. Furthermore, because there is no known human ortholog of this enzyme, it an attractive antifungal target for drug discovery to treat candidiasis with minimal adverse side effects and toxicity.…”

“…ICL has been explored as a potential drug target in other pathogenic fungi [18], Mycobacterium tuberculosis [19], [20], [21], and Burkholderia species [22], [23]. Importantly, no human ortholog of this pathway or its respective enzymes has been identified, which makes it a promising antifungal target to treat C. albicans infection.…”

Suvanine Sesterterpenes from a Tropical Sponge Coscinoderma sp. Inhibit Isocitrate Lyase in the Glyoxylate Cycle

“…5.0, Prism) was used to fit the measured data and determine IC 50 (inhibitory concentration for 50% activity) values [ 25 ]. The representative dose–response curves of suvanine sesterterpenes ( 1 , 2 , and 4 ) against the ICL enzyme were compared to that of known ICL inhibitors, 3-nitropropinate and itaconate [ 12 , 26 ] ( Figure 2 ).…”

“…In previous years, a wide array of works developing potential ICL inhibitors have been reported. Various 3-nitropropionamides, pyruvate-isoniazid analogs, salicylanilide and benzanilide derivatives showed a potential to inhibit M. tuberculosis ICL [ 11 , 12 ]. As part of efforts to discover pharmacologically effective ICL inhibitors, many marine-derived natural compounds were isolated and evaluated against C. albicans and M. grisea ICL [ 13 , 14 ].…”

Potential Inhibitors for Isocitrate Lyase ofMycobacterium tuberculosisand Non-M. tuberculosis: A Summary

“…The ultimate goal of this strategy is not only to look for new inhibitors, but also to improve the inhibitory potential of existing ones. A thorough review for synthetic compounds targeting MTB ICL is available [ 33 , 34 ]. The review articles have reviewed the synthetic compounds such as pthalazinyl derivatives [ 35 ], phthalazin-4-ylacetamides [ 36 ], 5-nitro-2-furoic acid hydrazones with furan-2-carbaldehyde [ 37 ], 5-Nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides [ 38 ], isatinyl thiosemicarbazones derivatives [ 39 ], and 3-nitropropionamide derivatives [ 40 ] with 45–61%, 40.62–66%, 86.8%, 45.7%, and 63.44% inhibition at 10 μ M and IC 50 of 0.1 μ M, respectively.…”