Protection of Mice From a Chlamydia trachomatis Vaginal Infection Using a Salicylidene Acylhydrazide, a Potential Microbicide

Slepenkin, Anatoly; Chu, Hencelyn; Elofsson, Mikael; Keyser, P. De; Peterson, Ellena M.

doi:10.1093/infdis/jir552

Cited by 39 publications

(40 citation statements)

References 32 publications

(42 reference statements)

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“…Slepenkin et al published an account of a salicylidene acylhydrazide protecting against infection in vivo, working with the sexually transmitted pathogen C. trachomatis (67). During the trial, the authors gave 51 mice 10 vaginal treatments with a salicylidene acylhydrazide, INP0341, or diluent alone (67).…”

Section: T3ss Inhibitors: a Recent History Of Discoverymentioning

confidence: 99%

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Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Duncan

Linington

Auerbuch

2012

Antimicrob Agents Chemother

105

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The recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by "magic bullet" drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

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Section: T3ss Inhibitors: a Recent History Of Discoverymentioning

confidence: 99%

“…During the trial, the authors gave 51 mice 10 vaginal treatments with a salicylidene acylhydrazide, INP0341, or diluent alone (67). The mice were infected with C. trachomatis 2 days after the first treatment, and INP0341 or sham control treatments continued for 5 days after infection (67).…”

Section: T3ss Inhibitors: a Recent History Of Discoverymentioning

confidence: 99%

Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Duncan

Linington

Auerbuch

2012

Antimicrob Agents Chemother

105

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“…Following these results we hypothesized that a hydrazone with effect on ExoS secretion should become further enhanced through complexation with Ga(III) and that this effect would be correlated to the metal chelation strength of the ligand. To test this hypothesis we selected a hydrazone, N'-(5-chloro-2-hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (INP0341, or ME0329), that previously has been described to have a good antibacterial effect against other Gramnegative bacteria [14,15], and that showed to have an effect against the T3SS in P. aeruginosa in preliminary experiments. We used P. aeruginosa as a relevant model organism in this context, since it is an opportunistic pathogen giving rise to a range of different infections in humans.…”

Section: Introductionmentioning

confidence: 99%

Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa

Hakobyan

Rzhepishevska

Björn

et al. 2016

Journal of Inorganic Biochemistry

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Development of antibiotic resistance in bacteria causes major challenges for our society and has prompted a great need for new and alternative treatment methods for infection. One promising approach is to target bacterial virulence using for example salicylidene acylhydrazides (hydrazones). Hydrazones coordinate metal ions such as Fe(III) and Ga(III) through a five-membered and a six-membered chelation ring. One suggested mode of action is via restricting bacterial Fe uptake. Thus, it was hypothesized that the chelating strength of these substances could be used to predict their biological activity on bacterial cells. This was investigated by comparing Ga chelation strength of two hydrazone complexes, as well as bacterial Ga uptake, biofilm formation, and virulence in the form of production and secretion of a toxin (ExoS) by Pseudomonas aeruginosa. Equilibrium constants for deprotonation and Ga(III) binding of the hydrazone N'-(5-chloro-2-hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (ME0329), with anti-virulence effect against P. aeruginosa, were determined and compared to bacterial siderophores and the previously described Ga(III) 2-oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (Ga-ME0163) and Ga-citrate complexes. In comparison with these two complexes, it was shown that the uptake of Ga(III) was higher from the Ga-ME0329 complex. The results further show that the Ga-ME0329 complex reduced ExoS expression and secretion to a higher extent than Ga-citrate, Ga-ME0163 or the non-coordinated hydrazone. However, the effect against biofilm formation by P. aeruginosa, by the ME0329 complex, was similar to Ga-citrate and lower than what has been reported for Ga-ME0163.

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“…High-content screening (HCS) uses cell-based assays, automated microscopy, and image analysis to collect complex information (4) and is well suited to screen for compounds for use against the obligate intracellular bacterium Chlamydia (5). Inhibitors of Chlamydia have been used to investigate the Chlamydia life cycle (6-11) and have been suggested for prevention of transmission (12)(13)(14).…”

mentioning

confidence: 99%

N -Acylated Derivatives of Sulfamethoxazole and Sulfafurazole Inhibit Intracellular Growth of Chlamydia trachomatis

Marwaha

Uvell

Salin

et al. 2014

Antimicrob Agents Chemother

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f Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

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Protection of Mice From a Chlamydia trachomatis Vaginal Infection Using a Salicylidene Acylhydrazide, a Potential Microbicide

Cited by 39 publications

References 32 publications

Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa

N -Acylated Derivatives of Sulfamethoxazole and Sulfafurazole Inhibit Intracellular Growth of Chlamydia trachomatis

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