title: Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity.
abstract: The global spread of anti-microbial resistance requires urgent attention, and diverse alternative strategies have been suggested to address this public health concern. Host-directed immunomodulatory therapies represent one approach that could reduce selection for resistant bacterial strains. Recently, the small molecule deubiquitinase inhibitor WP1130 was reported as a potential anti-infective drug against important human food-borne pathogens, notably Listeria monocytogenes and noroviruses. Utilization of WP1130 itself is limited due to poor solubility, but given the potential of this new compound, we initiated an iterative rational design approach to synthesize new derivatives with increased solubility that retained anti-infective activity. Here, we test a small library of novel synthetic molecules based on the structure of the parent compound, WP1130, for anti-infective activity in vitro. Our studies identify a promising candidate, compound 9, which reduced intracellular growth of L. monocytogenes at concentrations that caused minimal cellular toxicity. Compound 9 itself had no bactericidal activity and only modestly slowed Listeria growth rate in liquid broth culture, suggesting that this drug acts as an anti-infective compound by modulating host-cell function. Moreover, this new compound also showed anti-infective activity against murine norovirus (MNV-1) and human norovirus, using the Norwalk virus replicon system. This small molecule inhibitor may provide a chemical platform for further development of therapeutic deubiquitinase inhibitors with broad-spectrum anti-infective activity.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Charbonneau
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Marta J
authors.initials: MJ
authors.lastname: Gonzalez-Hernandez
authors.affiliation: Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Wobus
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Mary X D
authors.initials: MX
authors.lastname: O'Riordan
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003487:Cyanoacrylates / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology*; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008970:Molecular Weight; D029322:Norovirus / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000998:Antiviral Agents; D003487:Cyanoacrylates; D011480:Protease Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; C519751:degrasyn; D064570:Ubiquitin-Specific Proteases
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