HDAC3 inhibitor RGFP966 controls bacterial growth and modulates macrophage signaling during Mycobacterium tuberculosis infection

Monica Campo, Sarah Heater, Glenna J. Peterson, Jason D. Simmons, Shawn J. Skerrett, Harriet Mayanja-Kizza, Catherine M. Stein, W. Henry Boom, Thomas R. Hawn

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Article number102062
JournalTuberculosis
Volume127
DOIs
StatePublished - Mar 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021

Keywords

  • Histone deacetylase inhibitors
  • Host-directed therapeutics
  • Tuberculosis

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