Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal mod...

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Bibliographic Details
Published in:Biomedicines 2023-07, Vol.11 (7), p.1975
Main Authors: Fan, Dongguang, Wang, Bin, Stelitano, Giovanni, Savková, Karin, Riabova, Olga, Shi, Rui, Wu, Xiaomei, Chiarelli, Laurent R, Mikušová, Katarína, Makarov, Vadim, Lu, Yu, Hong, Yuzhi, Qiao, Chunhua
Format: Article
Language:English
Subjects:
Animal models
anti-tubercular agents
Antibiotic resistance
Bioavailability
Cell walls
Chromatography
Comparative analysis
D-Ribose
Disease resistance
DprE1 inhibitor
Drug resistance
Drug resistance in microorganisms
Enzymes
in vivo activity
Infectious diseases
Laboratory animals
Metabolism
Monosaccharides
Oxidases
Pharmacokinetics
Physicochemical properties
Solubility
structure activity relationship
Sugars
Tuberculosis
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Summary:Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound displays improved solubility and bioavailability compared to the lead compound. Additionally, compound shows Mtb-killing ability in an acute infection mouse model.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11071975