Toxin-antitoxin system

Bakterije su razvile iznimnu sposobnost prilagodbe na različite životne uvjete. Uz pomoć raznih sustava i mehanizama daju brz stanični odgovor na stresore, tretman antibiotikom, stanje gladi i ostale nepovoljne uvjete. Jedan takav sustav pronađen je u kromosomu mnogih bakterija, ali i u plazmidima i drugim pokretnim elementima. Sastoji se od dva gena od kojih jedan kodira otrov, a drugi protuotrov. Otrovi su proteini koji interferiraju s vitalnim procesima, čime inhibiraju rast ili uzrokuju smrt stanice. Aktivnost otrova reguliraju protuotrovi koji ih direktno ili indirektno inhibiraju. S obzirom na to kakvim mehanizmom protuotrov djeluje na otrov, razlikujemo šest tipova sustava otrov-protuotrov. Sustavi otrovprotuotrov tipa II imaju i mehanizam transkripcijske autoregulacije, koji je reguliran omjerom otrov: protuotrov. Stanični signali poput (p)ppGpp i proteini koji sudjeluju u staničnom odgovoru na stres također mogu regulirati transkripciju sustava otrov-protuotrov. Sustavi otrovprotuotrov koji se nalaze na plazmidima i drugim pokretnim elementima sudjeluju u stabilizaciji istih preko PSK mehanizma, dok oni na kromosomu imaju ulogu u eng. abortive infection i eng. persister formation. Glavni modelni organizam u istraživanju sustava otrov-protuotrov je soj gamaproteobakterije E. coli K-12. Sustavi otrov-protuotrov pokazali su se kao mogući uzrok sve češćeg neuspjelog tretmana antibioticima. Razlog tome je perzistentno stanje koje omogućava bakterijama da se nakon tretmana antibiotikom ponovno razvije normalno rastuća populacija. U tijeku su istraživanja novih vrsta lijekova koji bi spriječili nastanak perzistentnog stanja. Međutim, i dalje nije razjašnjeno koja je točno veza između određenih sustava otrov-protuotrov i neke biološke funkcije, odnosno kada i kako točno će neki sustav reagirati na određene uvjete.During the course of their evolution, bacteria have developed an astounding ability to adapt to a wide variety of living conditions. Various cellular systems and mechanisms ensure rapid response to different stressors, antibiotics, starvation and other unfavourable conditions. One such system has been discovered both in chromosomal DNA and in mobile elements of bacteria. It's loci consist of two genes: one encodes a toxin, and the other encodes a cognate antitoxin. Toxins are proteins that interfere with vital cullular functions to inhibit bacterial growth, and can even cause apoptosis. Antitoxin control their cognate toxin through direct interactions, or through transcriptional and translational regulation of expression. Six types of these system have been described based on the nature of the antitoxin and how it inhibits the activity of the toxin protein. Transcriptional autoregulation of toxin-antitoxin (TA) modules is particularly prevalent among type II TA modules and is based on a T:A ratio. Transcription of TA modules can also be regulated by celullar signals such as (p)ppGpp and SOS signaling proteins. Some TA modules can prevent the loss of plasmids or other mobile elements from bacterial cultures through a mechanism known as PSK. TA modules found in chromosomal DNA of bacteria could be involved in abortive infection and persister formation mechanism. E. coli K-12 is the main model organims in research of TA system. Increasingly appreciated reason that antibiotics fail is because the bacteria use TA system to evade antibiotic exposure by persistent mechanism. Once relieved, the persisters can revert back to the actively growing state and repopulate the original population. Given the pressing need for new antibiotics, novel approaches that target TA systems and the processes that regulate them are warranted. One of the problems is that despite significant efforts, it has remained unclear how the molecular features and activities of TA modules are translated into biological function