Abstract
Drug-resistant pathogens have presented increasing challenges to the discovery and development of new antibacterial agents. The type III secretion system (T3SS), existing in bacterial chromosomes or plasmids, is one of the most complicated protein secretion systems. T3SSs of animal and plant pathogens possess many highly conserved main structural components comprised of about 20 proteins. Many Gram-negative bacteria carry T3SS as a major virulence determinant, and using the T3SS, the bacteria secrete and inject effector proteins into target host cells, triggering disease symptoms. Therefore, T3SS has emerged as an attractive target for antimicrobial therapeutics. In recent years, many T3SS-targeting small-molecule inhibitors have been discovered; these inhibitors prevent the bacteria from injecting effector proteins and from causing pathophysiology in host cells. Targeting the virulence of Gram-negative pathogens, rather than their survival, is an innovative and promising approach that may greatly reduce selection pressures on pathogens to develop drug-resistant mutations. This article summarizes recent progress in the search for promising small-molecule T3SS inhibitors that target the secretion and translocation of bacterial effector proteins.
Highlights
Antibiotic therapy is the most commonly-used strategy to control infectious pathogens, most antibiotics affect cellular processes of microorganisms and, kill them, which becomes a strong selective pressure to develop resistance against antibiotics [1]
LcrF is a member of the AraC family of transcription activators [33] and is a multiple adaptational response (MAR) transcription factor associated with virulence in Yersinia pestis and
In the past few years, extraordinary efforts have been made by a number of laboratories to discover new T3SS inhibitors as potential anti-infective agents
Summary
Antibiotic therapy is the most commonly-used strategy to control infectious pathogens, most antibiotics affect cellular processes of microorganisms and, kill them, which becomes a strong selective pressure to develop resistance against antibiotics [1]. The discovery of bacterial secretion systems is an important milestone in studies on the mechanisms of bacterial pathogenesis Most enterobacterial pathogens, such as animal pathogens Pseudomonas aeruginosa, Salmonella Typhimurium and Yersinia pestis, and plant pathogens Dickeya dadantii, Erwinia amylovora and Pseudomonas syringae, possess at least one type III secretion system (T3SS) as a major virulence determinant [4,5]. Through this protein secretion/injection system, pathogens translocate their virulence factors (effectors) directly into host cells, enabling infection by subverting cells’ defense mechanisms [6,7]. T3SS represents a appealing target for antimicrobial agents, because the antimicrobial therapies using T3SS-specific inhibitors would affect the virulence rather than the viability of pathogens, creating low selective pressure for developing drug resistance [2,3]
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