Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen

• Published in: ACS infectious diseases Vol. 2; no. 3; pp. 231 - 239
• Main Authors: Dutta, Noton K, He, Rongjun, Pinn, Michael L, He, Yantao, Burrows, Francis, Zhang, Zhong-Yin, Karakousis, Petros C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.03.2016
• Subjects: inhibitors; guinea pig; isoniazid; sterilizing; activity; pyrazinamide; chemotherapy; protein tyrosine phosphatases; virulence factors; Mycobacterium tuberculosis; rifampin; pharmacokinetics; bactericidal
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.5b00133

Novel drugs are required to shorten the duration of treatment for tuberculosis (TB) and to combat the emergence of drug resistance. One approach has been to identify and target Mycobacterium tuberculosis (Mtb) virulence factors, which promote the establishment of TB infection and pathogenesis. Mtb produces a number of virulence factors, including two protein tyrosine phosphatases (PTPs), mPTPA and mPTPB, to evade the antimicrobial functions of host macrophages. To assess the therapeutic potential of targeting the virulent Mtb PTPs, we developed highly potent and selective inhibitors of mPTPA (L335-M34) and mPTPB (L01-Z08) with drug-like properties. We tested the bactericidal activity of L335-M34 and L01-Z08 alone or together in combination with the standard anti-tubercular regimen of isoniazid–rifampicin–pyrazinamide (HRZ) in the guinea pig model of chronic TB infection, which faithfully recapitulates some of the key histological features of human TB lesions. Following a single dose of L335-M34 50 mg/kg and L01-Z08 20 mg/kg, plasma levels were maintained at levels 10-fold greater than the biochemical IC50 for 12–24 h. Although neither PTP inhibitor alone significantly enhanced the antibacterial activity of HRZ, dual inhibition of mPTPA and mPTPB in combination with HRZ showed modest synergy, even after 2 weeks of treatment. After 6 weeks of treatment, the degree of lung inflammation correlated with the bactericidal activity of each drug regimen. This study highlights the potential utility of targeting Mtb virulence factors, and specifically the Mtb PTPs, as a strategy for enhancing the activity of standard anti-TB treatment.