title: In silico-based high-throughput screen for discovery of novel combinations for tuberculosis treatment.
abstract: There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an in silico kinetic platform in which the major metabolic pathways in Mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The in silico-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Ragini
authors.initials: R
authors.lastname: Singh
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Khandelwal
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Malancha
authors.initials: M
authors.lastname: Karmarkar
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Robert
authors.initials: R
authors.lastname: Nanduri
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: K R
authors.initials: KR
authors.lastname: Prabhakar
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Narasimha
authors.initials: N
authors.lastname: Rao
authors.affiliation: AstraZeneca India Pvt. Ltd., Bengaluru, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Anand
authors.initials: A
authors.lastname: Anandkumar
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India bala.subramanian@cellworksgroup.com.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: Cellworks Research India Pvt. Ltd., Bengaluru, India.
authors.forename: Santanu
authors.initials: S
authors.lastname: Datta
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D004977:Ethambutol / Q000627:therapeutic use*; D007538:Isoniazid / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D012293:Rifampin / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin