Di Bonaventura Giovanni, Lupetti Veronica, Pompilio Arianna
Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.
Center for Advanced Studies and Technology, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.
Antibiotics (Basel). 2024 Jul 12;13(7):642. doi: 10.3390/antibiotics13070642.
lung infections in cystic fibrosis (CF) patients represent a therapeutic challenge due to antibiotic resistance. Repurposing existing drugs is a promising approach for identifying new antimicrobials. A crucial factor in successful drug repurposing is using assay conditions that mirror the site of infection. Here, the impact of growth conditions on the anti- activity of a library of 3386 compounds was evaluated. To this, after 24 h exposure, the survival rate of CF RP73 planktonic cells was assessed spectrophotometrically under "CF-like" (artificial CF sputum, pH 6.8, 5% CO) and enriched (Tryptone Soya Broth, pH 7.2, and aerobiosis) conditions. Among non-antibiotic compounds (n = 3127), 13.4% were active regardless of growth conditions, although only 3.2% had comparable activity; 4% and 6.2% were more active under CF-like or enriched conditions, respectively. Interestingly, 22.1% and 26.6% were active exclusively under CF-like and enriched conditions, respectively. Notably, 7 and 12 hits caused 100% killing under CF-like and enriched conditions, respectively. Among antibiotics (n = 234), 42.3% were active under both conditions, although only 18.4% showed comparable activity; 9.4% and 14.5% were more active under CF-like and enriched conditions, respectively. Interestingly, 23% and 16.6% were active exclusively under CF-like and enriched conditions, respectively. Sulphonamides showed higher activity under CF-like conditions, whereas tetracyclines, fluoroquinolones, and macrolides were more effective under enriched settings. Our findings indicated that growth conditions significantly affect the anti- activity of antibiotics and non-antibiotic drugs. Consequently, repurposing studies and susceptibility tests should be performed under physicochemical conditions that the pathogen tackles at the site of infection.
由于抗生素耐药性，囊性纤维化（CF）患者的肺部感染构成了一项治疗挑战。重新利用现有药物是识别新型抗菌药物的一种有前景的方法。成功进行药物重新利用的一个关键因素是使用能够反映感染部位的检测条件。在此，评估了生长条件对3386种化合物文库抗菌活性的影响。为此，在暴露24小时后，在“类CF”（人工CF痰液，pH 6.8，5%二氧化碳）和富集（胰蛋白胨大豆肉汤，pH 7.2，需氧）条件下，通过分光光度法评估CF RP73浮游细胞的存活率。在非抗生素化合物（n = 3127）中，13.4%无论生长条件如何均有活性，尽管只有3.2%具有相当的活性；分别有4%和6.2%在类CF或富集条件下活性更高。有趣的是，分别有22.1%和26.6%仅在类CF和富集条件下有活性。值得注意的是，分别有7种和12种命中化合物在类CF和富集条件下导致100%的杀伤。在抗生素（n = 234）中，42.3%在两种条件下均有活性，尽管只有18.4%表现出相当的活性；分别有9.4%和14.5%在类CF和富集条件下活性更高。有趣的是，分别有23%和16.6%仅在类CF和富集条件下有活性。磺胺类药物在类CF条件下表现出更高的活性，而四环素、氟喹诺酮类和大环内酯类在富集条件下更有效。我们的研究结果表明，生长条件显著影响抗生素和非抗生素药物的抗菌活性。因此，重新利用研究和药敏试验应在病原体在感染部位所面临的物理化学条件下进行。
