Monica Campo1, Sarah Heater2, Glenna J Peterson3, Jason D Simmons3, Shawn J Skerrett3, Harriet Mayanja-Kizza4, Catherine M Stein5, W Henry Boom6, Thomas R Hawn3. 1. Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: mcampo@uw.edu. 2. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. 3. Department of Medicine, University of Washington, Seattle, WA, USA. 4. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. 5. Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Medicine, School of Medicine, Makerere University and Mulago Hospital, Kampala, Uganda. 6. Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Abstract
RATIONALE: Host-directed therapeutics for Mycobacterium tuberculosis (Mtb) offer potential strategies for combatting antibiotic resistance and for killing non-replicating bacilli. Phenylbutyrate, a partially selective histone-deacetylase (HDAC) inhibitor, was previously shown to control Mtb growth and alter macrophage inflammatory pathways at 2-4 mM concentrations. OBJECTIVE: To identify a more potent and selective HDAC inhibitor that modulates macrophage responses to mycobacteria and has direct antibacterial effects against Mtb. METHODS: We used cellular approaches to characterize the role of pharmacologic inhibition of HDAC3 on Mtb growth and Mtb-induced peripheral and alveolar macrophage immune functions. MEASUREMENTS AND MAIN RESULTS: RGFP966, an HDAC3 inhibitor, controlled Mtb, BCG and M. avium growth directly in broth culture and in human peripheral blood monocyte-derived and alveolar macrophages with an MIC50 of approximately 5-10 μM. In contrast, RGFP966 did not inhibit growth of several other intracellular and extracellular bacteria. We also found that RGFP966 modulated macrophage pro-inflammatory cytokine secretion in response to Mtb infection with decreased IL6 and TNF secretion. CONCLUSIONS: We identified a potent and selective small molecule inhibitor of HDAC3 with direct antimicrobial activity against Mtb and modulation of macrophage signaling pathways.
RATIONALE: Host-directed therapeutics for Mycobacterium tuberculosis (Mtb) offer potential strategies for combatting antibiotic resistance and for killing non-replicating bacilli. Phenylbutyrate, a partially selective histone-deacetylase (HDAC) inhibitor, was previously shown to control Mtb growth and alter macrophage inflammatory pathways at 2-4 mM concentrations. OBJECTIVE: To identify a more potent and selective HDAC inhibitor that modulates macrophage responses to mycobacteria and has direct antibacterial effects against Mtb. METHODS: We used cellular approaches to characterize the role of pharmacologic inhibition of HDAC3 on Mtb growth and Mtb-induced peripheral and alveolar macrophage immune functions. MEASUREMENTS AND MAIN RESULTS: RGFP966, an HDAC3 inhibitor, controlled Mtb, BCG and M. avium growth directly in broth culture and in human peripheral blood monocyte-derived and alveolar macrophages with an MIC50 of approximately 5-10 μM. In contrast, RGFP966 did not inhibit growth of several other intracellular and extracellular bacteria. We also found that RGFP966 modulated macrophage pro-inflammatory cytokine secretion in response to Mtb infection with decreased IL6 and TNF secretion. CONCLUSIONS: We identified a potent and selective small molecule inhibitor of HDAC3 with direct antimicrobial activity against Mtb and modulation of macrophage signaling pathways.
Authors: John-Demian Sauer; Katia Sotelo-Troha; Jakob von Moltke; Kathryn M Monroe; Chris S Rae; Sky W Brubaker; Mamoru Hyodo; Yoshihiro Hayakawa; Joshua J Woodward; Daniel A Portnoy; Russell E Vance Journal: Infect Immun Date: 2010-11-22 Impact factor: 3.441
Authors: George A Diaz; Andreas Schulze; Nicola Longo; William Rhead; Annette Feigenbaum; Derek Wong; J Lawrence Merritt; William Berquist; Renata C Gallagher; Dennis Bartholomew; Shawn E McCandless; Wendy E Smith; Cary O Harding; Roberto Zori; Uta Lichter-Konecki; Jerry Vockley; Colleen Canavan; Thomas Vescio; Robert J Holt; Susan A Berry Journal: Mol Genet Metab Date: 2019-07-10 Impact factor: 4.797
Authors: Payam Nahid; Susan E Dorman; Narges Alipanah; Pennan M Barry; Jan L Brozek; Adithya Cattamanchi; Lelia H Chaisson; Richard E Chaisson; Charles L Daley; Malgosia Grzemska; Julie M Higashi; Christine S Ho; Philip C Hopewell; Salmaan A Keshavjee; Christian Lienhardt; Richard Menzies; Cynthia Merrifield; Masahiro Narita; Rick O'Brien; Charles A Peloquin; Ann Raftery; Jussi Saukkonen; H Simon Schaaf; Giovanni Sotgiu; Jeffrey R Starke; Giovanni Battista Migliori; Andrew Vernon Journal: Clin Infect Dis Date: 2016-08-10 Impact factor: 9.079