Bacterial Carbonic Anhydrase Inhibitor CAI0019 Demonstrates Efficacy in Enterococcus faecium Septicemic Peritonitis Mouse Model While Sparing the Microbiome

Vancomycin-resistant enterococci are multidrug-resistant
bacteria
that as of 2021 continue to pervade the U.S. healthcare system as
the second-most prevalent source of healthcare-acquired infections
behind Escherichia coli. Given the limited treatment options for vancomycin-resistant enterococci
and growing concerns about antibiotic-induced gut microbiome dysbiosis,
there is an urgent need for narrow-spectrum antibiotics that can selectively
target vancomycin-resistant enterococci while preserving the integrity
of the gut microbiome. Previous studies have demonstrated the in vivo
potential of orally dosed acetazolamide-based compounds to reduce
vancomycin-resistant enterococci bioburden in the gastrointestinal
tract and internal organs of mice. However, while it is hypothesized
that these molecules inhibit bacterial carbonic anhydrases, the exact
target of the acetazolamide scaffold in vancomycin-resistant enterococci
has remained unconfirmed. Additionally, the impact of the scaffold
on in vivo gut microbiome diversity remains uncharacterized. The work
herein reports the chemoproteomic identification of α-carbonic
anhydrase as the primary target of the acetazolamide scaffold in E. faecium and presents its
uniqueness as a narrow-spectrum antibiotic target that can be exploited
by CAI0019, a lead acetazolamide derivative with in vivo efficacy,
while sparing gut microbiome diversity in mice. This work presents
compelling data that not only confirm α-carbonic anhydrase as
an antibiotic target in Enterococcus but also demonstrate
that narrow-spectrum in vivo antienterococcal efficacy can be achieved
through targeting α-carbonic anhydrase such that gut commensal
microbiota remain unimpacted.