Project Details
Projekt
Preclinical development of α-aminooxyhydroxamic acid derivatives targeting drug-resistant Mycobacterium tuberculosis
Subject Area
Pharmacy
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 410897573
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains the world’s deadliest bacterial infectious disease. In 2015, about 10.4 million people developed active disease and about 1.8 million death occurred. Resistance of Mtb against available drugs is now widespread and progressing further. Multidrug-resistant M. tuberculosis strains (MDR-TB), which are resistant to the first-line antibiotics isoniazid and rifampicin, have developed into extensively-drug resistant (XDR-TB) strains that are additionally resistant to any fluoroquinolone and one of the three injectable drugs capreomycin, kanamycin, and amikacin. Some of these strains are resistant to all available antitubercular drugs and are virtually untreatable. Only two new anti-TB, drugs bedaquiline and delamanid, have been approved in the last 45 year. Both drugs display novel mechanisms of action but are associated with several drawbacks such as hERG toxicity and high lipophilicity. Hence, these drugs cannot be widely implemented into TB treatment regimens and have obtained only restricted approval for treatment of MDR-TB patients so far.Novel alpha-aminooxyhydroxamic acid derivatives identified during our preliminary studies exhibited very interesting properties that make them promising drug lead candidates: submicromolar antibacterial potency against Mtb including clinical XDR isolates, virtually no cytotoxicity towards human cells, low or no resistance development for some derivatives, potent synergistic activity with clinical anti-TB drugs, and established robust synthesis methods that allow medicinal chemical optimization and provision of sufficient amounts of substances for in vitro and in vivo testing as well as functional characterizations. In addition, none of the tested derivatives showed antibacterial activity (i.e. MIC > 100 micrometre in microbroth dilution assays using Müller-Hinton broth) against a panel of other Gram-positive and Gram-negative bacteria, indicating high antitubercular specificity.Considering these highly interesting properties, the overall objective of this project is now to understand and improve the antimycobacterial potential of alpha-aminooxyhydroxamic acid derivatives and to identify their cellular molecular target and the underlying mode-of-action.
DFG Programme
Research Grants
