thiostrepton and Bacterial-Infections

The bacterial thiopeptide thiostrepton (TS) is used as a veterinary medicine to treat bacterial infections. TS is a protein translation inhibitor, essentially active against Gram-positive bacteria and some Gram-negative bacteria. In procaryotes, TS abrogates binding of GTPase elongation factors to the 70S ribosome, by altering the structure of rRNA-L11 protein complexes. TS exerts also antimalarial effects by disrupting protein synthesis in the apicoplast genome of Plasmodium falciparum. Interestingly, the drug targets both the infectious pathogen (bacteria or parasite) and host cell, by inducing endoplasmic reticulum stress-mediated autophagy which contributes to enhance the host cell defense. In addition, TS has been characterized as a potent chemical inhibitor of the oncogenic transcription factor FoxM1, frequently overexpressed in cancers or other diseases. The capacity of TS to crosslink FoxM1, and a few other proteins such as peroxiredoxin 3 (PRX3) and the 19S proteasome, contributes to the anticancer effects of the thiopeptide. The anticancer activities of TS evidenced using diverse tumor cell lines, in vivo models and drug combinations are reviewed here, together with the implicated targets and mechanisms. The difficulty to formulate TS is a drag on the pharmaceutical development of the natural product. However, the design of hemisynthetic analogues and the use of micellar drug delivery systems should facilitate a broader utilization of the compound in human and veterinary medicines. This review shed light on the many pharmacological properties of TS, with the objective to promote its use as a pharmacological tool and medicinal product.

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Bacterial Infections; Humans; Signal Transduction; Thiostrepton

The thiopeptides are a family of ribosomally synthesized and post-translationally modified peptide metabolites, and the vast majority of thiopeptides characterized to date possess one highly modified macrocycle. A few members, including thiostrepton A, harbor a second macrocycle that incorporates a quinaldic acid moiety and the four N-terminal residues of the peptide. The antibacterial properties of thiostrepton A are well established, and its recently discovered ability to inhibit the proteasome has additional implications for the development of antimalarial and anticancer therapeutics. We have conducted the saturation mutagenesis of Ala2 in the precursor peptide, TsrA, to examine which variants can be transformed into a mature thiostrepton analogue. Although the thiostrepton biosynthetic system is somewhat restrictive toward substitutions at the second residue, eight thiostrepton Ala2 analogues were isolated. The TsrA Ala2Ile and Ala2Val variants were largely channeled through an alternate processing pathway wherein the first residue of the core peptide, Ile1, is removed, and the resulting thiostrepton analogues bear quinaldic acid macrocycles abridged by one residue. This is the first report revealing that quinaldic acid loop size is amenable to alteration during the course of thiostrepton biosynthesis. Both the antibacterial and proteasome inhibitory properties of the thiostrepton Ala2 analogues were examined. While the identity of the residue at the second position of the core peptide influences thiostrepton biosynthesis, our report suggests it may not be crucial for antibacterial and proteasome inhibitory properties of the full-length variants. In contrast, the contracted quinaldic acid loop can, to differing degrees, affect both types of biological activity.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Quinolines; Streptomyces; Thiostrepton

The seventh residue of thiostrepton is predicted to be critical for antibacterial activity. Substitution of Thr7 in the thiostrepton precursor peptide disrupts both biological activity and the successful biosynthesis of analogs.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Mutagenesis; Mutation; Streptomyces; Thiostrepton; Threonine