Click chemistry and T3SS Inhibition: Mechanistic Insights into Targeted Anti-Infective Strategies
DOI:
https://doi.org/10.18192/osurj.v5i2.8049Abstract
Antimicrobial resistance is a leading cause of death worldwide and only expected to worsen in
the coming years. New antimicrobial drugs with new mechanisms of action are desperately
needed to address this problem. The Type III Secretion System (T3SS) is a promising new drug
target due to its critical role in several bacterial infections including chlamydia, diarrheal disease,
plague, and lung infections in cystic fibrosis. The T3SS is a megadalton protein complex in the
shape of a syringe that secretes pathogen proteins into the host cell, facilitating the invasion and
colonization of the host. Small molecules with T3SS-disrupting activity would block infection
without killing the pathogen, making them a promising new class of anti-virulence drugs. A
recent high-throughput cell-based screen has identified one of the first compounds known to
strongly inhibit T3SS activity. The inhibition is indirect with C5 treatment inducing a 3 to 57
fold downregulation of expression of genes encoding the T3SS. However, the mechanism of
downregulation has remained elusive.
Click chemistry is a synthetic strategy that relies on a class of highly efficient, selective, and
reliable reactions to join smaller molecular building blocks together. A Noble Prize-winning
example was the copper-catalyzed aside-alkyne cycloaddition in Chemistry in 2022.
Click or bio-orthogonal approaches synchronizes with the Type 3 Secretion System (T3SS) as it
reduces the T3SS effector since they allow site-specific, minimal, and non-disruptive tagging of
proteins with small chemical handles, such as azide, alkyne, strained alkyne and alkene. After
incorporation of the handle, a second step called “click ligation” occurs, therefore, this two-step
approach preserves the native function better than direct fusion of bulky tags. Instead of killing
bacteria, small molecules can be designed to inhibit T3SS function, blocking the pathogen’s
ability to evade the immune system. By designing a narrow spectrum of drugs, this can disarm
pathogens with lower resistance pressure.
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