A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis

Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to life-long sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first generation compound KSK120, inhibits the developmental cycle of Chlamydia resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis and the effect was only observable upon re-infection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen C. muridarum and in C. caviae. The molecular target of KSK213 may thus be different in C. trachomatis or non-essential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNAse III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

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Effects ofMentha suaveolensEssential Oil onChlamydia trachomatis

BioMed Research International ◽

10.1155/2015/508071 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Rosa Sessa ◽

Marisa Di Pietro ◽

Fiorenzo De Santis ◽

Simone Filardo ◽

Rino Ragno ◽

...

Keyword(s):

Chlamydia Trachomatis ◽

Substantial Reduction ◽

Developmental Cycle ◽

Elementary Body ◽

Promising Candidate ◽

Common Cause ◽

Sexually Transmitted ◽

Reticulate Body ◽

Preventative Strategy

Chlamydia trachomatis, the most common cause of sexually transmitted bacterial infection worldwide, has a unique biphasic developmental cycle alternating between the infectious elementary body and the replicative reticulate body.C. trachomatisis responsible for severe reproductive complications including pelvic inflammatory disease, ectopic pregnancy, and obstructive infertility. The aim of our study was to evaluate whetherMentha suaveolensessential oil (EOMS) can be considered as a promising candidate for preventingC. trachomatisinfection. Specifically, we investigated thein vitroeffects of EOMS towardsC. trachomatisanalysing the different phases of chlamydial developmental cycle. Our results demonstrated that EOMS was effective towardsC. trachomatis, whereby it not only inactivated infectious elementary bodies but also inhibited chlamydial replication. Our study also revealed the effectiveness of EOMS, in combination with erythromycin, towardsC. trachomatiswith a substantial reduction in the minimum effect dose of antibiotic. In conclusion, EOMS treatment may represent a preventative strategy since it may reduceC. trachomatistransmission in the population and, thereby, reduce the number of new chlamydial infections and risk of developing of severe sequelae.

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Chlamydial infection and disease in the koala

Microbiology Australia ◽

10.1071/ma05065 ◽

2005 ◽

Vol 26 (2) ◽

pp. 65 ◽

Cited By ~ 3

Author(s):

Peter Timms

Keyword(s):

Chlamydia Trachomatis ◽

Chlamydial Infection ◽

Developmental Cycle ◽

Elementary Body ◽

Obligate Intracellular ◽

Molecular Approaches ◽

Reticulate Body ◽

Wide Range ◽

The Family ◽

Serious Disease

Chlamydiae are obligate intracellular bacterial pathogens able to infect and cause serious disease in humans, birds and a remarkably wide range of warm and cold-blooded animals. The family Chlamydiaciae have traditionally been defined by their unique biphasic developmental cycle, involving the interconversion between an extracellular survival form, the elementary body and an intracellular replicative form, the reticulate body. However, as with many other bacteria, molecular approaches including 16SrRNA sequence are becoming the standard of choice. As a consequence, the chlamydiae are in a taxonomic state of flux. Prior to 1999, the family Chlamydiaceae consisted of one genus, Chlamydia, and four species, Chlamydia trachomatis, C. psittaci, C. pecorum and C. pneumoniae. In 1999, Everett et al proposed a reclassification of Chlamydia into two genera (Chlamydia and Chlamydophila) and nine species (Chlamydia trachomatis, C. suis, and C. muridarum and Chlamydophila psittaci, C. pneumoniae, C. felis, C. pecorum, C. abortus, and C. caviae). While some of these species are thought to be host specific (C. suis ? pigs, C. muridarum ? mice, C. felis ? cats, C. caviae ? guinea pigs) many are known to infect and cause disease in a wide range of hosts.

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Role for GrgA in Regulation of σ28-Dependent Transcription in the Obligate Intracellular Bacterial PathogenChlamydia trachomatis

Journal of Bacteriology ◽

10.1128/jb.00298-18 ◽

2018 ◽

Vol 200 (20) ◽

Cited By ~ 3

Author(s):

Malhar Desai ◽

Wurihan Wurihan ◽

Rong Di ◽

Joseph D. Fondell ◽

Bryce E. Nickels ◽

...

Keyword(s):

Transcription Factor ◽

Chlamydia Trachomatis ◽

Sigma Factor ◽

Bacterial Pathogen ◽

Direct Interaction ◽

Developmental Cycle ◽

Content Type ◽

Sexually Transmitted ◽

Obligate Intracellular ◽

Specific Transcription Factor

ABSTRACTThe obligate intracellular bacterial pathogenChlamydia trachomatishas a unique developmental cycle consisting of two contrasting cellular forms. Whereas the primaryChlamydiasigma factor, σ66, is involved in the expression of the majority of chlamydial genes throughout the developmental cycle, expression of several late genes requires the alternative sigma factor, σ28. In prior work, we identified GrgA as aChlamydia-specific transcription factor that activates σ66-dependent transcription by binding DNA and interacting with a nonconserved region (NCR) of σ66. Here, we extend these findings by showing GrgA can also activate σ28-dependent transcription through direct interaction with σ28. We measure the binding affinity of GrgA for both σ66and σ28, and we identify regions of GrgA important for σ28-dependent transcription. Similar to results obtained with σ66, we find that GrgA's interaction with σ28involves an NCR located upstream of conserved region 2 of σ28. Our findings suggest that GrgA is an important regulator of both σ66- and σ28-dependent transcription inC. trachomatisand further highlight NCRs of bacterial RNA polymerase as targets for regulatory factors unique to particular organisms.IMPORTANCEChlamydia trachomatisis the number one sexually transmitted bacterial pathogen worldwide. A substantial proportion ofC. trachomatis-infected women develop infertility, pelvic inflammatory syndrome, and other serious complications.C. trachomatisis also a leading infectious cause of blindness in underdeveloped countries. The pathogen has a unique developmental cycle that is transcriptionally regulated. The discovery of an expanded role for theChlamydia-specific transcription factor GrgA helps us understand the progression of the chlamydial developmental cycle.

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Emergence of DIM-1 and KPC-1 Genes Associated Carbapenem-Resistant Pseudomonas Aeruginosa Isolates in Three Major Hospitals in Hanoi, Vietnam (2010-2015)

10.21203/rs.3.rs-143498/v1 ◽

2021 ◽

Author(s):

Tran Hai Anh ◽

Tran Huy Hoang ◽

Vu Thi Ngoc Bich ◽

Trinh Son Tung ◽

Tran Dieu Linh ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Treatment Options ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Phylogenetic Tree Analysis ◽

Antibiotic Resistant ◽

Hospital Acquired Infection ◽

Healthcare Settings ◽

Carbapenem Resistant ◽

Hospital Acquired

Abstract Background: Multidrug-resistant bacteria including carbapenem resistant Pseudomonas aeruginosa are recognised as an important cause of hospital-acquired infections worldwide. To determine the molecular characterisation and antibiotic resistant genes associated with carbapenem-resistant P. aeruginosa. Methods: we conducted whole-genome sequencing and phylogenetic analysis of 72 carbapenem-resistant P. aeruginosa isolated from hospital-acquired infection patients from 2010 to 2015 in three major hospitals in Hanoi, Vietnam. Results: We identified three variants of IMP genes, among which IMP-15 gene was the most frequent (n= 34) in comparison to IMP-26 (n= 2) and IMP-51 (n=12). We observed two isolates with imipenem MIC >128mg/L that co-harboured IMP-15 and DIM-1 genes and seven isolates (imipenem MIC> 128mg/L) with KPC-1 gene from the same hospital. MLST data showed that sequence types (ST) of 72 isolates were classified into 18 STs and phylogenetic tree analysis divided these isolates into nine groups. Conclusion: Our results provide evidence that not only IMP-26, but other variants of IMPs like IMP-15 and IMP-51 genes and several STs (ST235, ST244, ST277, ST310, ST773 and ST3151) have been disseminated in health care settings in Vietnam. Also, we report the first finding in Vietnam that two isolates belonging to ST1240 and ST3340 harboured two important carbapenemase genes (IMP-15 and, DIM-1) and seven isolates belonging to ST3151 of P. aeruginosa carried the KPC-1 gene, which could be a potential cause of seriously restricted available treatment options in healthcare settings.

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Targetable nano-delivery vehicles to deliver anti-bacterial small acid-soluble spore protein (SASP) genes

Emerging Topics in Life Sciences ◽

10.1042/etls20210147 ◽

2021 ◽

Author(s):

Anne M. L. Barnard ◽

James A. Cass

Keyword(s):

Bacterial Infections ◽

Treatment Options ◽

Resistant Bacteria ◽

Wild Type ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

Specific Target ◽

Delivery Vehicles ◽

New Treatment

Interest in phage-based therapeutics is increasing, at least in part due to the need for new treatment options for infections caused by antibiotic-resistant bacteria. It is possible to use wild-type (WT) phages to treat bacterial infections, but it is also possible to modify WT phages to generate therapeutics with improved features. Here, we will discuss features of Phico Therapeutics’ SASPject technology, which modifies phages for use as targetable nano-delivery vehicles (NDV), to introduce antibacterial Small Acid Soluble Spore Protein (SASP) genes into specific target bacteria.

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Genitourethral infections caused by D–K serotypes ofChlamydia trachomatis

Orvosi Hetilap ◽

10.1556/oh.2015.30078 ◽

2015 ◽

Vol 156 (1) ◽

pp. 19-23

Author(s):

Péter Holló ◽

Hajnalka Jókai ◽

Krisztina Herszényi ◽

Sarolta Kárpáti

Keyword(s):

Chlamydia Trachomatis ◽

Current Knowledge ◽

Treatment Options ◽

Clinical Signs ◽

Diagnostic Techniques ◽

Treatment Protocols ◽

Sexually Transmitted ◽

Screening Programs ◽

Leading Role ◽

Special Circumstances

Sexually transmitted infections of the urogenital tract are most commonly caused by the intracellular bacteria Chlamydia trachomatis worldwide, resulting the clinical picture of acute urethritis in men as well as urethritis and endocervicitis in women. As women often present with few symptoms only or a completely symptom-free disease course, one of the most important long-term complications is chronic pelvic inflammatory disease often followed by the development of infertility caused by chronic scar formation. Well-organized screening programs are considered to have a leading role in the prevention of disease spreading and long lasting unwanted complications. Antibiotic treatment options are often influenced by special circumstances, such as pregnancy and several complicated clinical forms. The aims of the authors are to give a concise review on the current knowledge regarding Chlamydia trachomatis infections and summarize typical clinical signs, modern diagnostic techniques as well as accepted treatment protocols and basic aspects of screening. Orv. Hetil., 2015, 156(1), 19–23.

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A potential role for GrgA in regulation of σ28-dependent transcription in the obligate intracellular bacterial pathogen Chlamydia trachomatis

10.1101/322701 ◽

2018 ◽

Cited By ~ 1

Author(s):

Malhar Desai ◽

Wurihan Wurihan ◽

Rong Di ◽

Joseph D. Fondell ◽

Bryce E. Nickels ◽

...

Keyword(s):

Chlamydia Trachomatis ◽

Sigma Factor ◽

Bacterial Pathogen ◽

Direct Interaction ◽

Developmental Cycle ◽

Sexually Transmitted ◽

Obligate Intracellular ◽

Bacterial Rna ◽

Important Regulator ◽

Conserved Region

ABSTRACTThe sexually transmitted obligate intracellular bacterial pathogen Chlamydia trachomatis has a unique developmental cycle consisting of two contrasting cellular forms. Whereas the primary Chlamydia sigma factor, σ66, is involved in the expression of the majority of chlamydial genes throughout the developmental cycle, expression of several late genes requires the alternative sigma factor σ28. In prior work we identified GrgA as a Chlamydia-specific transcription factor that activates σ66-dependent transcription by binding DNA and interacting with a non-conserved region (NCR) of σ66. Here, we extend these findings by showing GrgA can also activate σ28-dependent transcription through direct interaction with σ28. We measure the binding affinity of GrgA for both σ66and σ28, and we identify regions of GrgA important for σ28-dependent transcription. Similar to results obtained with σ66, we find that GrgA’s interaction with σ28 involves a NCR located upstream of conserved region 2 of σ28. Our findings suggest GrgA is an important regulator of both σ66- and σ28-dependent transcription in C. trachomatis and further highlight NCRs of bacterial RNA polymerase as targets for regulatory factors unique to particular organisms.

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Levels and Treatment Options for Enteric and Antibiotic-Resistant Bacteria in Sewage from Sisimiut, Greenland

ISCORD 2013 ◽

10.1061/9780784412978.074 ◽

2013 ◽

Author(s):

Pernille Erland Jensen ◽

Ragnhildur Gunnarsdottir ◽

Henrik Rasmus Andersen ◽

Grith Martinsen ◽

Ellen Stærk Nicolajsen ◽

...

Keyword(s):

Treatment Options ◽

Resistant Bacteria ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant

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Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

10.1101/199422 ◽

2017 ◽

Cited By ~ 2

Author(s):

Nathan Wlodarchak ◽

Nathan Teachout ◽

Rebecca Procknow ◽

Jeff Beczkiewicz ◽

Adam Schaenzer ◽

...

Keyword(s):

Kinase Inhibitors ◽

Treatment Options ◽

Computational Modelling ◽

Resistant Bacteria ◽

Antibiotic Resistant Bacteria ◽

Novel Therapy ◽

Antibiotic Resistant ◽

Antibiotic Development ◽

Human Kinase ◽

Pathogenic Actinomycetes

AbstractAntibiotic resistant bacteria are an increasing global problem, and pathogenic actinomycetes and firmicutes are particularly challenging obstacles. These pathogens share several eukaryotic-like kinases that present antibiotic development opportunities. We used computational modelling to identify human kinase inhibitors that could be repurposed towards bacteria as part of a novel combination therapy. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel x-ray structure confirmed that the inhibitors bind as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity towards Mycobacteria and Nocardia, and normally ineffective β-lactams can potentiate IPAs to more efficiently inhibit growth of these pathogens. Collectively, our data show thatin silicomodeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can synergize with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.

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Cell Type Development in Chlamydia trachomatis Follows a Program Intrinsic to the Reticulate Body

10.1101/2020.03.13.991687 ◽

2020 ◽

Author(s):

Travis J Chiarelli ◽

Nicole A Grieshaber ◽

Anders Omsland ◽

Christopher H Remien ◽

Scott S Grieshaber

Keyword(s):

Cell Division ◽

Chlamydia Trachomatis ◽

Mathematical Models ◽

Live Cell Imaging ◽

Cell Imaging ◽

Developmental Cycle ◽

Cell Type ◽

Obligate Intracellular ◽

Reticulate Body ◽

A Cell

AbstractThe obligate intracellular bacterial pathogen Chlamydia trachomatis (Ctr) is reliant on an unusual developmental cycle consisting of two cell forms termed the elementary body (EB) and the reticulate body (RB). The EB is infectious and utilizes a type III secretion system and preformed effector proteins during invasion, but does not replicate. The RB replicates in the host cell but is non-infectious. This developmental cycle is central to chlamydial pathogenesis. In this study we developed mathematical models of the chlamydial developmental cycle that account for potential factors influencing the timing of RB to EB cell type switching during infection. Our models predicted that two broad categories of regulatory signals for RB to EB development could be differentiated experimentally; an “intrinsic” cell autonomous program inherent to each RB or an “extrinsic” environmental signal to which RBs respond. To experimentally differentiate between these hypotheses, we tracked the expression of Ctr developmental specific promoters using fluorescent reporters and live cell imaging. These experiments indicated that EB production was not influenced by increased MOI or by superinfection, suggesting the cycle follows an intrinsic program that is not influenced by environmental factors. Additionally, live cell imaging of these promoter constructs revealed that EB development is a multistep process linked to RB growth rate and cell division. The formation of EBs followed a cell type gene expression progression with the promoters for euo and ihtA active in RBs, while the promoter for hctA was active in early EBs/intermediate cells and finally the promoters for the true late genes, hctB, scc2, and tarp active in the maturing EB.ImportanceChlamydia trachomatis is an obligate intracellular bacteria that can cause trachoma, cervicitis, urethritis, salpingitis, and pelvic inflammatory disease. To establish infection in host cells Chlamydia must complete a multi cell type developmental cycle. The developmental cycle consists of two specialized cells; the EB which mediates infection of new cells and the RB which replicates and eventually produces more EB cells to mediate the next round of infection. By developing and testing mathematical models to discriminate between two competing hypotheses for the nature of the signal controlling RB to EB cell type switching. We demonstrate that RB to EB development follows a cell autonomous program that does not respond to environmental cues. Additionally, we show that RB to EB development is a function of cell growth and cell division. This study serves to further our understanding of the chlamydial developmental cycle that is central to the bacterium’s pathogenesis.

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