Research Article: Development of Chlamydial Type III Secretion System Inhibitors for Suppression of Acute and Chronic Forms of Chlamydial Infection


Date Published: , 2012

Publisher: A.I. Gordeyev

Author(s): N.A. Zigangirova, E.S. Zayakin, L.N. Kapotina, E.A. Kost, L.V. Didenko, D.Y. Davydova, J.P. Rumyanceva, A.L. Gintsburg.

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Abstract

The Type III secretion system (T3SS) is currently considered to be one of the
main pathogenicity factors in Gram-negative bacteria, which exhibit different
types of parasitizing activity. The presence of this structure is essential for
the development of an acute infection; the chronicity of the infection is
fundamentally dependent upon its functioning. In this regard, T3TS is one of the
most promising targets for the development of broad-spectrum antimicrobial drugs
that do not develop resistance and are efficacious for the acute and chronic
forms of infection. The mechanism of action in drug development is based on the
specific inhibition of T3SS, which should interrupt the infectious process,
thereby enabling the immune system to eliminate the pathogen. As a result of
pilot screening using specific cellular and bacterial tests, followed by
chemical optimization and detailed characterization of the biological activity,
a new class of chlamydial T3SS inhibitors was obtained. The selected compounds
have obvious advantages over the currently available inhibitors of T3SS
pathogens thanks to the high inhibitory activity of these compounds with minimal
damaging effects on eukaryotic cells. Preclinical trials of the selected
inhibitors are currently under way.

Partial Text

Chlamydia are Gram-negative bacteria that parasitize intercellularly. T wo species of
Chlamydia are common pathogenic agents responsible for diseases in humans. The
Chlamydia infection caused by Chlamydia trachomatis is the most
prevalent among sexually transmitted diseases,causing over 100 million new cases of
the disease annually [1]. According to the
WHO, the number of people in the world infected with Chlamydia by the most
conservative estimate has reached a billion; the number of infections is on a steady
increase even in the developed world. The fraction of cases of respiratory
chlamydiosis caused by C. pneumoniae in the total structure of
pneumonias stands at 20%; epidemic outbursts of this infection occur in European
countries every 4–7 years (according to WHO data). As a result, up to 80% of
the world population are infected with respiratory chlamydiosis during their lives.
Chronic chlamydioses pose the most serious problem; it is a proven fact that these
diseases act as a mechanism triggering severe chronic diseases, such as asthma,
atherosclerosis, arthritis, female and male infertility, as well as pregnancy
pathologies [2, 3].


The type III secretion system detected only in pathogenic bacteria was selected for
use as a target for the search for new antibacterial drugs that would demonstrate
efficacy with respect to both acute and chronic infections. The formation of this
secretory apparatus, the so-called “molecular syringe,” starts after
contact with a eukaryotic cell. It forms a pore in the target cell membrane,
resulting in the direct penetration of the pathogenicity factors into the host
cell’s cytoplasm [20]. T3SS can also
function upon intracellular localization of the pathogen. The transport of the
pathogenic factors results in cytoskeletal rearrangement, apoptosis inhibition,
modification of the apparatus of transcription and translation in the eukaryotic
cells, modulation of cytokine production and other processes in the host cell which
facilitates pathogen invasion, blockage of host protection, and the establishment of
continuous persistence [21]. T3SS is
absolutely essential for the development of an acute infectious process; the
chronization of the infection fundamentally depends on how it functions. Thus, the
specific inhibition of the T3SS function is expected to interrupt the infectious
process both at early stages and upon a chronic course, thus allowing the immune
system to eliminate the pathogen.


 

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