Woods Angela L, Parker David, Glick Meir M, Peng Yunshan, Lenoir Francois, Mulligan Evan, Yu Vincent, Piizzi Grazia, Lister Troy, Lilly Maria-Dawn, Dzink-Fox JoAnn, Jansen Johanna M, Ryder Neil S, Dean Charles R, Smith Thomas M
Infectious Diseases, Novartis Institutes for Biomedical Research Inc, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research Inc, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
ACS Omega. 2022 Feb 1;7(6):5401-5414. doi: 10.1021/acsomega.1c06633. eCollection 2022 Feb 15.
The continuing emergence of antibacterial resistance reduces the effectiveness of antibiotics and drives an ongoing search for effective replacements. Screening compound libraries for antibacterial activity in standard growth media has been extensively explored and may be showing diminishing returns. Inhibition of bacterial targets that are selectively important under in vivo (infection) conditions and, therefore, would be missed by conventional in vitro screens might be an alternative. Surrogate host models of infection, however, are often not suitable for high-throughput screens. Here, we adapted a medium-throughput surrogate host model that was successfully used to identify inhibitors of a hyperviscous strain to a high-throughput format and screened circa 1.2 million compounds. The screen was robust and identified confirmed hits from different chemical classes with potent inhibition of growth in the presence of that lacked any appreciable direct antibacterial activity. Several of these appeared to inhibit capsule/mucoidy, which are key virulence factors in hypervirulent . A weakly antibacterial inhibitor of LpxC (essential for the synthesis of the lipid A moiety of lipopolysaccharides) also appeared to be more active in the presence of , which is consistent with the role of LPS in virulence as well as viability in .
抗菌耐药性的不断出现降低了抗生素的有效性，并推动人们持续寻找有效的替代药物。在标准生长培养基中筛选具有抗菌活性的化合物库已得到广泛探索，但其回报可能正在减少。抑制在体内（感染）条件下具有选择性重要性、因此会被传统体外筛选遗漏的细菌靶点可能是一种替代方法。然而，感染的替代宿主模型通常不适合高通量筛选。在这里，我们将一种成功用于鉴定高粘性菌株抑制剂的中通量替代宿主模型调整为高通量形式，并筛选了约120万种化合物。该筛选方法稳健，从不同化学类别中鉴定出了确证的活性化合物，这些化合物在缺乏任何明显直接抗菌活性的情况下对生长具有强效抑制作用。其中几种化合物似乎抑制了荚膜/黏液形成，而荚膜/黏液是高毒力菌株中的关键毒力因子。一种对LpxC（脂多糖脂质A部分合成所必需）具有弱抗菌活性的抑制剂在[具体条件]存在时似乎也更具活性，这与LPS在毒力以及[具体微生物]生存能力中的作用一致。
