Small molecule inhibitors of type III secretion in <i>Yersinia</i> block the <i>Chlamydia pneumoniae</i> infection cycle

Bailey, Leslie; Gylfe, Åsa; Sundin, Charlotta; Muschiol, Sandra; Elofsson, Mikael; Nordström, Peter; Henriques‐Normark, Birgitta; Lugert, Raimond; Waldenström, Anders; Wolf‐Watz, Hans; Bergström, Sven

doi:10.1016/j.febslet.2007.01.013

Cited by 95 publications

(93 citation statements)

References 22 publications

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“…We recently reported that salicylidene acylhydrazides (SAHs) act as inhibitors of the Yersinia pseudotuberculosis T3S (15,16). We further showed that the SAH variants INP0341 and INP0010 also inhibit Chlamydia growth and development, observations that have been corroborated by other groups (17,18,20,28). These findings suggest that T3S activity is essential for Chlamydia (22).…”

Section: Resultssupporting

confidence: 71%

“…Small-molecule screens performed by Kauppi et al identified salicylidene acylhydrazides (SAHs) as inhibitors of the Yersinia pseudotuberculosis T3S (15,16). Subsequent studies indicate that SAHs block Chlamydia growth but not entry into cells (17)(18)(19)(20)(21), which supports the prevalent notion that the T3S is essential during the middle and late stages of the Chlamydia developmental cycle (22). Subsequent studies indicate that secretion or localization of predicted T3S effectors is altered by SAHs (19,(23)(24)(25)(26).…”

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confidence: 48%

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Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity

et al. 2013

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Section: Resultssupporting

confidence: 71%

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confidence: 48%

Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity

et al. 2013

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“…The targeting of nonvital bacterial processes decreases selection pressure, making mutation-based resistance to these therapies less likely (3). Investigations of the type III secretion system (T3SS), where promising molecules-some of which showed broad-spectrum activity for various bacterial pathogens-were identified through whole-cell-based high-throughput screens, have had success with this strategy (4)(5)(6).…”

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confidence: 99%

Novel Role for PilNO in Type IV Pilus Retraction Revealed by Alignment Subcomplex Mutations

et al. 2015

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Type IV pili (T4P) are dynamic protein filaments that mediate bacterial adhesion, biofilm formation, and twitching motility. The highly conserved PilMNOP proteins form an inner membrane alignment subcomplex required for function of the T4P system, though their exact roles are unclear. Three potential interaction interfaces for PilNO were identified: core-core, coiled coils (CC), and the transmembrane segments (TMSs). A high-confidence PilNO heterodimer model was used to select key residues for mutation, and the resulting effects on protein-protein interactions were examined both in a bacterial two-hybrid (BTH) system and in their native Pseudomonas aeruginosa context. Mutations in the oppositely charged CC regions or the TMS disrupted PilNO heterodimer formation in the BTH assay, while up to six combined mutations in the core failed to disrupt the interaction. When the mutations were introduced into the P. aeruginosa chromosome at the pilN or pilO locus, specific changes at each of the three interfaces-including core mutations that failed to disrupt interactions in the BTH system-abrogated surface piliation and/or impaired twitching motility. Unexpectedly, specific CC mutants were hyperpiliated but nonmotile, a hallmark of pilus retraction defects. These data suggest that PilNO participate in both the extension and retraction of T4P. Our findings support a model of multiple, precise interaction interfaces between PilNO; emphasize the importance of studying protein function in a minimally perturbed context and stoichiometry; and highlight potential target sites for development of small-molecule inhibitors of the T4P system. IMPORTANCEPseudomonas aeruginosa is an opportunistic pathogen that uses type IV pili (T4P) for host attachment. The T4P machinery is composed of four cell envelope-spanning subcomplexes. PilN and PilO heterodimers are part of the alignment subcomplex and essential for T4P function. Three potential PilNO interaction interfaces (the core-core, coiled-coil, and transmembrane segment interfaces) were probed using site-directed mutagenesis followed by functional assays in an Escherichia coli two-hybrid system and in P. aeruginosa. Several mutations blocked T4P assembly and/or motility, including two that revealed a novel role for PilNO in pilus retraction, while other mutations affected extension dynamics. These critical PilNO interaction interfaces represent novel targets for small-molecule inhibitors with the potential to disrupt T4P function.A larming increases in antibiotic resistance have prompted the search for alternative strategies to combat bacterial infection (1). Genomic strategies designed to identify essential bacterial targets have been informative but less successful for drug development than originally predicted due to high mutation rates and resistance (2). Alternative strategies-such as phage therapy and the use of "antivirulence" drugs that target bacterial factors involved in pathogenesis-show promise since they can effectively disarm bacteria, which are then more easily...

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“…Although secretion activity has not been achieved, this promising approach could facilitate functional studies in a genetically tractable background. The use of chemical genetics has been attempted with chlamydiae by using small-molecule inhibitors of the NF-T3SS (86)(87)(88)(89) and CopN (30). Inhibition of infectivity by inhibitors of the NF-T3SS is reversed by exogenous iron, and chlamydiae that are resistant to the inhibitors contain mutations in hemG (90), making the link to T3S activity unclear.…”

Section: Future Prospectsmentioning

confidence: 99%

New Frontiers in Type III Secretion Biology: the Chlamydia Perspective

2014

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Members of the order Chlamydiales comprise a group of exquisitely evolved parasites of eukaryotic hosts that extends from single-celled amoeba to mammals. The most notable are human pathogens and include the agent of oculogenital disease Chlamydia trachomatis, the respiratory pathogen C. pneumoniae, and the zoonotic agent C. psittaci. All of these species are obligate intracellular bacteria that develop within parasitophorous vesicles termed inclusions. This demanding lifestyle necessitates orchestrated entry into nonphagocytic cells, creation of a privileged intracellular niche, and subversion of potent host defenses. All chlamydial genomes contain the coding capacity for a nonflagellar type III secretion system, and this mechanism has arisen as an essential contributor to chlamydial virulence. The emergence of tractable approaches to the genetic manipulation of chlamydiae raises the possibility of explosive progress in understanding this important contributor to chlamydial pathogenesis. This minireview considers challenges and recent advances that have revealed how chlamydiae have maintained conserved aspects of T3S while exploiting diversification to yield a system that exerts a fundamental role in the unique biology of Chlamydia species.

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Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle

Cited by 95 publications

References 22 publications

Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity

Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity

Novel Role for PilNO in Type IV Pilus Retraction Revealed by Alignment Subcomplex Mutations

New Frontiers in Type III Secretion Biology: the Chlamydia Perspective

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