Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads

Kandale, Ajit; Patel, Khushboo; Hussein, Waleed M.; Wun, Shun Jie; Zheng, Shan; Tan, Lendl; West, Nicholas P.; Schenk, Gerhard; Guddat, L.W.; McGeary, Ross P.

doi:10.1021/acs.jmedchem.0c01919

Cited by 12 publications

(20 citation statements)

References 40 publications

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“…These compounds thus provide excellent starting points to further develop leads for novel treatments for infectious diseases. For instance, variants of IpOHA have recently been reported to be significantly more potent towards KARI from M. tuberculosis and similar modifications may thus also enhance the inhibitory potency of this compound for DHADs [22] …”

Section: Discussionmentioning

confidence: 99%

“…IpOHA derivatives that may bypass the time-dependence of their interactions with KARI are currently being designed and may also become relevant as DHAD inhibitors. [18,20,22] Conclusions DHAD, along with other enzymes from the BCAA pathway (Figure 1), is an attractive target for novel anti-microbial drug discovery. DHAD is still a relatively poorly characterised enzyme, and thus the characterisation of SaDHAD and CjDHAD provides significant functional and catalytic insight into these DHADs.…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

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Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

Bayaraa

Gaete

Sutiono

et al. 2022

Chemistry A European J

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There is an urgent global need for the development of novel therapeutics to combat the rise of various antibioticresistant superbugs. Enzymes of the branched-chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti-microbial drug development. Dihydroxy-acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an FeÀ S cluster for catalytic activity and has recently also gained attention as a catalyst in cell-free enzyme cascades. Two types of FeÀ S clusters have been identified in DHADs, i.e. [2FeÀ 2S] and [4FeÀ 4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ~19,000-fold increase with k cat as high as ~6.7 s À 1 ). Inductively-coupled plasma-optical emission spectroscopy (ICP-OES) measurements are consistent with the presence of [4FeÀ 4S] clusters in both enzymes. N-isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K i = 7.8 and 51.6 μM, respectively) and CjDHAD (K i = 32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti-microbial chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Enzyme Inhibitionmentioning

confidence: 99%

Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

Bayaraa

Gaete

Sutiono

et al. 2022

Chemistry A European J

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“…Further, noctyl ester derivative of compound 33 has been found fivefold more potent activity than N-hydroxy-N-isopropyloxamate (potent inhibitor of KARI with K i of 97.7 nM) along with MIC 90 of 2.3 μM (H 37 Rv). [61] Figure 10. Pyrrolidine as anti-TB agents.…”

Section: Othersmentioning

confidence: 99%

“…reported N ‐hydroxy‐ N ‐isopropyloxamate analogues ( 33 ) as inhibiting ketol‐acid reductoisomerase (KARI) inhibitor as anti‐TB scaffold with K i value of 19.7 nM. Further, n ‐octyl ester derivative of compound 33 has been found fivefold more potent activity than N ‐hydroxy‐ N ‐isopropyloxamate (potent inhibitor of KARI with K i of 97.7 nM) along with MIC 90 of 2.3 μM (H 37 Rv) [61] …”

Section: Introductionmentioning

confidence: 99%

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

et al. 2022

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Tuberculosis (TB) has been the highly contagious airborne disease caused by Mycobacterium tuberculosis and the major leading infectious disease with the higher upsurge of morbidity and mortality. Owing to problems in the current regimen for TB and emergence of drug resistance strains, there is a strong necessity for development of new anti-TB drugs with better efficacy, reduced duration of action, along with improved patient compliance. Towards this, the scaffolds reported in 2021 with anti-tubercular activity such as benzofuran, benzothiazinone, benzimidazoles, indole, piperidine, piperazine, pyrazole, pyridine, pyrimidine, pyrrolidine, quinoxaline, triazole, etc. have been critically reviewed along with their structureactivity relationships, mode of actions with anticipations of intuitions to design the newer anti-mycobacterial scaffolds.The present work provide the organized coverage of diversified scaffolds with anti-tubercular profile reported in 2021 along with the insightful discussion on their merits and demerits. The mode of anti-tubercular action against Mycobacterium tuberculosis strains have been presented keeping in mind the novel drug candidates against drug resistant strains [a] Dr.

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“…The enzyme is therefore necessary for amino acid prototrophy. Because of its importance in bacteria, plants and fungi, but its absence in metazoans, the enzyme receives increasing attention for the design of antibiotics, herbicides and fungicides [2][3][4]. On the other hand, branched-chain amino acids are valuable compounds for the food, cosmetic and pharmaceutical industries, with a constantly increasing global market (e.g., L-valine: average annual increase rate >5% [5,6]).…”

Section: Introductionmentioning

confidence: 99%

Structural Rearrangements of a Dodecameric Ketol-Acid Reductoisomerase Isolated from a Marine Thermophilic Methanogen

et al. 2021

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Ketol-acid reductoisomerase (KARI) orchestrates the biosynthesis of branched-chain amino acids, an elementary reaction in prototrophic organisms as well as a valuable process in biotechnology. Bacterial KARIs belonging to class I organise as dimers or dodecamers and were intensively studied to understand their remarkable specificity towards NADH or NADPH, but also to develop antibiotics. Here, we present the first structural study on a KARI natively isolated from a methanogenic archaea. The dodecameric structure of 0.44-MDa was obtained in two different conformations, an open and close state refined to a resolution of 2.2-Å and 2.1-Å, respectively. These structures illustrate the conformational movement required for substrate and coenzyme binding. While the close state presents the complete NADP bound in front of a partially occupied Mg2+-site, the Mg2+-free open state contains a tartrate at the nicotinamide location and a bound NADP with the adenine-nicotinamide protruding out of the active site. Structural comparisons show a very high conservation of the active site environment and detailed analyses point towards few specific residues required for the dodecamerisation. These residues are not conserved in other dodecameric KARIs that stabilise their trimeric interface differently, suggesting that dodecamerisation, the cellular role of which is still unknown, might have occurred several times in the evolution of KARIs.

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Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads

Cited by 12 publications

References 40 publications

Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

Structural Rearrangements of a Dodecameric Ketol-Acid Reductoisomerase Isolated from a Marine Thermophilic Methanogen

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