Bulge oligonucleotide as an inhibitory agent of bacterial topoisomerase I

Abstract

Bacterial topoisomerase I (Btopo I) was defined as potential target for discovery of new antibacterial compounds. Various oligonucleotides containing bulge structure were designed and synthesised as inhibitors to Btopo I in this investigation. The results of this study demonstrated that the designed oligonucleotides display high inhibitory efficiency on the activity of Btopo I and the inhibitory effect could be modulated by the amount of bulge DNA bases. The most efficient one among them showed an IC50 value of 63.1 nM in its inhibition on the activity of Btopo I. In addition, our studies confirmed that the designed oligonucleotide would induce irreversible damages to Btopo I and without any effects occur to eukaryotic topoisomerase I. It is our hope that the results provided in these studies could provide a novel way to inhibit Btopo I.

Type IA Topoisomerases as Targets for Infectious Disease Treatments

“…The first step in the catalytic cycle of the enzyme is the recognition of the single-stranded regions in duplex DNA [ 139 ]. A series of 84 bp double-stranded oligonucleotides with variations in the number of bulge bases in a single-stranded loop were synthesized and tested for inhibition of the relaxation activity of E. coli topoisomerase I [ 140 ]. Inhibition efficiency improves as the size of the single-stranded loop increases from 1 to 10 base in length with IC 50 reaching 63.1 nM.…”

“…Inhibition of eukaryotic calf thymus topoisomerase I relaxation activity was not observed. It was hypothesized that because the single-stranded loops in the bulge oligonucleotides are not base-paired, the bulge oligonucleotides may be acting as irreversible competitive inhibitors [ 140 ].…”

“…A general advantage of DNA molecules is the low toxicity for the host compared to conventional drugs. The major drawback is that the ability of DNA molecules to penetrate the bacterial cell wall is very low, so more advancements in drug delivery research is needed [ 140 , 141 ].…”

Antibacterial Therapeutic Agents Composed of Functional Biological Molecules

“…Yang and coworkers reported that linear oligonucleotides containing mismatch or bulge can act as the irreversible inhibitors of bacterial topoisomerase I [66,67], but no direct evidence such as the formation of covalent complex between DNA and proteins was provided in their studies. In our recent studies, particularly designed small DNA circles with high bending stress were synthesized [68].…”

Новые Стратегии И Молекулярные Мишени Для Противомикробных Препаратов Нового Поколения

“…Ñêîíñòðóèðîâàííûå îëèãîíóêëåîòèäû ñ õàðàêòåðíîé ïåòëåé â ñòðóêòóðå ïðèâîäÿò ê íåîáðàòèìûì ïîâðåaeäåíèÿì áàêòåðèàëüíîé Topo I áåç êàêèõ-ëèáî ýôôåêòîâ â îòíîøåíèè ýóêàðèîòè÷åñêîé òîïîèçîìåðàçû I. Ïðîáëåìà ïðîäâèaeåíèÿ ìîëåêóëû â êëèíè÷åñêóþ ïðàêòèêó ñâÿçàíà ñ ïëîõîé ïðîíèöàåìîñòüþ âíóòðü áàêòåðèàëüíîé êëåòêè, èññëåäîâàòåëè âîçëàãàþò íàäåaeäû íà íàíîòåõíîëîãèè è ôàðìàöåâòè÷åñêèå ïîäõîäû [54].…”