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Small-Molecule Inhibitors of Haemophilus influenzae IgA1 Protease

Livia Shehaj1, Santosh K Choudary1, Kamlesh M Makwana1

  • 1Department of Chemistry , Tufts University , 62 Talbot Avenue , Medford , Massachusetts 02155 , United States.

ACS Infectious Diseases
|April 25, 2019
PubMed

Insights

Researchers discovered novel small molecule inhibitors for nontypeable Haemophilus influenzae IgA1 proteases. These inhibitors offer a promising therapeutic strategy against antibiotic-resistant bacterial infections.

Area of Science:

  • Microbiology and Infectious Diseases
  • Drug Discovery and Pharmacology

Background:

  • Nontypeable *Haemophilus influenzae* (*H. influenzae*) strains are a growing global health concern, exacerbated by rising antibiotic resistance.
  • Virulence factors, such as IgA1 proteases, are attractive therapeutic targets to circumvent resistance mechanisms.
  • Limited research exists on pharmacological inhibitors for IgA1 proteases, crucial for bacterial invasion and immune evasion.

Purpose of the Study:

  • To discover and characterize the first small molecule, nonpeptidic inhibitors of *H. influenzae* IgA1 proteases.
  • To evaluate the potential of these inhibitors as therapeutics against antibiotic-resistant *H. influenzae*.

Main Methods:

  • Screening of over 47,000 compounds using a biochemical assay with recombinant *H. influenzae* IgA1 protease.
  • Structure-activity relationship studies to optimize inhibitor potency and selectivity.
  • Testing dose-dependent inhibition against clinical isolates of IgA1 protease variants.

Main Results:

  • Identification of a hit compound with micromolar potency against *H. influenzae* IgA1 protease.
  • Development of improved inhibitors with enhanced potency and selectivity over other serine proteases.
  • Demonstrated dose-dependent inhibition of four distinct IgA1 protease variants from clinical isolates.

Conclusions:

  • The newly discovered small molecule inhibitors represent a promising new class of therapeutics for antibiotic-resistant *H. influenzae* infections.
  • These inhibitors can serve as valuable research tools to investigate the role of IgA1 proteases in mucosal tissue colonization and infection.
Keywords:
FRET assayIgA1 proteaseantibacterial resistancehigh-throughput screeningprotease inhibitors

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