Targeting the Type II Secretion System: Development, Optimization, and Validation of a High-Throughput Screen for the Identification of Small Molecule Inhibitors

Frontiers in Cellular and Infection Microbiology
Ursula WaackMaria Sandkvist

Abstract

Nosocomial pathogens that develop multidrug resistance present an increasing problem for healthcare facilities. Due to its rapid rise in antibiotic resistance, Acinetobacter baumannii is one of the most concerning gram-negative species. A. baumannii typically infects immune compromised individuals resulting in a variety of outcomes, including pneumonia and bacteremia. Using a murine model for bacteremia, we have previously shown that the type II secretion system (T2SS) contributes to in vivo fitness of A. baumannii. Here, we provide support for a role of the T2SS in protecting A. baumannii from human complement as deletion of the T2SS gene gspD resulted in a 100-fold reduction in surviving cells when incubated with human serum. This effect was abrogated in the absence of Factor B, a component of the alternative pathway of complement activation, indicating that the T2SS protects A. baumannii against the alternative complement pathway. Because inactivation of the T2SS results in loss of secretion of multiple enzymes, reduced in vivo fitness, and increased sensitivity to human complement, the T2SS may be a suitable target for therapeutic intervention. Accordingly, we developed and optimized a whole-cell high-throughput screening (...Continue Reading

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Related Concepts

In Vivo
Biochemical Pathway
Acinetobacter calcoaceticus
Treatment Protocols
Bacterial Proteins
Orlistat
Enzymes, antithrombotic
High Throughput Screening
Murine
Amorphophallus baumannii

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