A 2-Pyridone Amide Inhibitor of Transcriptional Activity in Chlamydia trachomatis

Abstract

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.

Differential Effects of Small Molecule Inhibitors on the Intracellular Chlamydia Infection

“…However, a limitation of these approaches is that they do not provide information about EB infectivity. It is possible that an inhibitor could affect EB maturation but not EB number ( 26 ), and such an effect will only be revealed by analysis with a combination of assays.…”

Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)

“…Other attempts to decrease the use of the antibiotic in genital chlamydiosis have arisen, as an attempt to protect the commensal flora. Recently, a 2-pyridone amide was discovered to inhibit transcription of crucial genes in progeny EBs, which became unable to differentiate into the RBs [ 144 ].…”

Therapeutic Options for Chlamydia trachomatis Infection: Present and Future

“…Recently, Núñez-Otero and his team, have developed and uncovered the second-generation 2-pyridone amide (KSK213) role in Ct infection control, with reduced toxicity for humans without disturbing the commensal flora. This molecule has revealed its effects in the transcription inhibition of crucial genes responsible for the differentiation from EB to RB, which could be a key control phase of Ct infection [ 94 ]. Additionally, there have been efforts to develop natural anti-chlamydial treatments based on extracts.…”