title: Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen.
abstract: 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 targetMycobacterium 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 antitubercular 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 50mg/kg and L01-Z08 20 mg/kg, plasma levels were maintained at levels 10-fold greater than the biochemical IC50for 12-24 hours. 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.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Noton K
authors.initials: NK
authors.lastname: Dutta
authors.affiliation: Department of Biochemistry and Molecular Biology Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Rongjun
authors.initials: R
authors.lastname: He
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pinn
authors.affiliation: Department of Biochemistry and Molecular Biology Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.affiliation: Aarden Pharmaceuticals, Inc. Indianapolis, IN, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
authors.affiliation: Department of Biochemistry and Molecular Biology Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
keywords: Mycobacterium tuberculosis; activity; bactericidal; chemotherapy; guinea pig; inhibitors; isoniazid; pharmacokinetics; protein tyrosine phosphatases; pyrazinamide; rifampin; sterilizing; virulence factors