title: FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria.
abstract: The dual effect of FtsZ inhibition and oxidative stress by a group of 1,2-dihydroquinolines that culminate in bactericidal effect on mycobacterium strains is demonstrated. They inhibited the non-pathogenic Mycobacterium smegmatis mc(2) 155 with MIC as low as 0.9 μg/mL and induced filamentation. Detailed studies revealed their ability to inhibit polymerization and GTPase activity of MtbFtsZ (Mycobacterial filamentous temperature sensitive Z) with an IC50 value of ∼40 μM. In addition to such target specific effects, these compounds exerted a global cellular effect by causing redox-imbalance that was evident from overproduction of ROS in treated cells. Such multi-targeting effect with one chemical scaffold has considerable significance in this era of emerging drug resistance and could offer promise in the development of new therapeutic agents against tuberculosis.
authors: Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600 036, India.
authors: Sridevi
authors: S
authors: Duggirala
authors: Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036, India.
authors: John Victor
authors: JV
authors: Napoleon
authors: Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600 036, India.
authors: Rakesh P
authors: RP
authors: Nankar
authors: Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036, India.
authors: V
authors: V
authors: Senu Adeeba
authors: Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036, India. Electronic address: mkm@iitm.ac.in.
authors: Muraleedharan K
authors: MK
authors: Manheri
authors: Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600 036, India. Electronic address: mukeshd@iitm.ac.in.
authors: Mukesh
authors: M
authors: Doble
mesh_terms: D001412:Bacillus subtilis / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D020558:GTP Phosphohydrolases / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C403008:1,4-dihydroquinone; D001426:Bacterial Proteins; D011809:Quinones; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases
keywords: Antimycobacterial activity; Dihydroquinolines; FtsZ inhibition; ROS