10018-94-7Relevant articles and documents
Inhibition of Mycobacterium tuberculosis InhA: Design, synthesis and evaluation of new di-triclosan derivatives
Alderwick, Luke J.,Armstrong, Tom,Lamont, Malcolm,Lanne, Alice,Thomas, Neil R.
supporting information, (2020/09/18)
Multi-drug resistant tuberculosis (MDR-TB) represents a growing problem for global healthcare systems. In addition to 1.3 million deaths in 2018, the World Health Organisation reported 484,000 new cases of MDR-TB. Isoniazid is a key anti-TB drug that inhibits InhA, a crucial enzyme in the cell wall biosynthesis pathway and identical in Mycobacterium tuberculosis and M. bovis. Isoniazid is a pro-drug which requires activation by the enzyme KatG, mutations in KatG prevent activation and confer INH-resistance. ‘Direct inhibitors’ of InhA are attractive as they would circumvent the main clinically observed resistance mechanisms. A library of new 1,5-triazoles, designed to mimic the structures of both triclosan molecules uniquely bound to InhA have been synthesised. The inhibitory activity of these compounds was evaluated using isolated enzyme assays with 2 (5-chloro-2-(4-(5-(((4-(4-chloro-2-hydroxyphenoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) exhibiting an IC50 of 5.6 μM. Whole-cell evaluation was also performed, with 11 (5-chloro-2-(4-(5-(((4-(cyclopropylmethoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) showing the greatest potency, with an MIC99 of 12.9 μM against M. bovis.
Identification of middle chain fatty Acyl-CoA Ligase responsible for the biosynthesis of 2-alkylmalonyl-CoAs for Polyketide extender unit
Miyazawa, Takeshi,Takahashi, Shunji,Kawata, Akihiro,Panthee, Suresh,Hayashi, Teruo,Shimizu, Takeshi,Nogawa, Toshihiko,Osada, Hiroyuki
, p. 26994 - 27011 (2015/11/17)
Background: Fatty acyl-CoA ligases involved in polyketide biosynthesis remain uncharacterized. Results: RevS classified in fatty acyl-AMP ligase clade was the middle chain fatty acyl-CoA ligase. Conclusion: RevS was responsible for 2-alkylmalonyl-CoA bios
Enzymatic synthesis of dilactone scaffold of antimycins
Sandy, Moriah,Rui, Zhe,Gallagher, Joe,Zhang, Wenjun
, p. 1956 - 1961 (2013/02/25)
Antimycins are a family of natural products possessing outstanding biological activities and unique structures, which have intrigued chemists for over a half century. The antimycin structural skeleton is built on a nine-membered dilactone ring containing one alkyl, one acyloxy, two methyl moieties, and an amide linkage connecting to a 3-formamidosalicylic acid. Although a biosynthetic gene cluster for antimycins was recently identified, the enzymatic logic that governs the synthesis of antimycins has not yet been revealed. In this work, the biosynthetic pathway for antimycins was dissected by both genetic and enzymatic studies for the first time. A minimum set of enzymes needed for generation of the antimycin dilactone scaffold were identified, featuring a hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line containing both cis- and trans-acting components. Several antimycin analogues were further produced using in vitro enzymatic total synthesis based on the substrate promiscuity of this NRPS-PKS machinery.