In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.

在通过将两个具有生物活性的支架融合成一种异源化学型来寻找新型杂交分子时，我们发现阿奇霉素和环丙沙星/加替沙星26j和26l的杂合体可以通过以类似于氟喹诺酮的方式中毒来抑制大肠杆菌回旋酶的超螺旋活性。。这可能适度地增强了它们的效力，相当于环丙沙星对组成型耐药性金黄色葡萄球菌的抵抗力，其生长不受大环内酯类药物的抑制。相反，引入喹啉（3-喹啉26b和6-喹啉26o）在阿奇霉素酰化物的6-OH处具有优化的刚性间隔基，对组成型耐药的金黄色葡萄球菌没有显着效力，尽管事实上以26o为例的含喹啉化合物与替利霉素一样对易感性，诱导性和抗外流病原体。涉及蛋白质合成抑制和DNA复制中毒的新型双重作用方式可能为恢复当前大环内酯类药物对组成型耐药临床分离株的抗菌活性铺平道路。