Selim Heba Mohammed Refat M, Gomaa Fatma Alzahraa M, Alshahrani Mohammad Y, Aboshanab Khaled M
Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Diriyah, Riyadh 11597, Saudi Arabia.
Department of Pharmacognosy and Medicinal Herbs, Faculty of Pharmacy, Al-Baha University, Al Baha, Saudi Arabia.
Curr Microbiol. 2025 Jan 3;82(2):68. doi: 10.1007/s00284-024-04049-1.
Fortimicins (FTMs) are fortamine-containing aminoglycoside antibiotics (AGAs) produced by M. olivasterospora DSM 43868 with excellent bactericidal activities against a wide range of Enterobacteriaceae and synergistic activity against multidrug-resistant (MDR) pathogens. Fortimicin-A (FTM-A), the most active member of FTMs, has the lowest susceptibility to inactivation by the aminoglycoside modifying enzymes (AMEs). Therefore, this study aimed to evaluate the antibacterial activity of FTM-A alone or in combination with other antibiotics against 18 non-clonal clinically relevant MDR Gram-positive and Gram-negative pathogens. This study also aimed to statistically optimize various environmental factors affecting its production using the response surface D-optimal design. Results showed that FTM-A/meropenem combination showed the highest synergistic bactericidal activity (61.1%) followed by its combination with cefotaxime and cefepime (38.8% each). However, FTM-A/gentamicin and FTM-A/doxycycline combinations showed mostly additive effects in 66.6% and 50% of the tested isolates, respectively. For FTM-A production optimization, maximum specific activity (µg/mg) to cell growth was achieved using aminoglycoside production medium followed by yeast extract-malt extract and M65 production medium. A D-optimal quadratic model consisting of 27 different media composition variations was used to predict an optimal composition for FTM-A production and verified experimentally. Lab verification of the model was carried out using HPLC analysis, resulting in a 10.5-fold increase in their production compared to the un-optimized conditions. The model revealed that the initial pH, incubation temperature, and incubation time significantly affected FTMs production (P-value < 0.05), however, the tested range of calcium carbonate 2-7 gL-1 and agitation rate (100-300 rpm) showed no significant effect (P-value > 0.05). In conclusion, the D-optimal design resulted in an effective model and optimized FTMs production on the shake flask level. FTM-A combinations with meropenem, cefotaxime, cefepime, and gentamicin showed mostly synergistic/additive effects and are advised for clinical evaluation.
福提霉素（FTMs）是由橄榄色链霉菌DSM 43868产生的含福他胺的氨基糖苷类抗生素（AGAs），对多种肠杆菌科细菌具有优异的杀菌活性，对多重耐药（MDR）病原体具有协同活性。福提霉素A（FTM-A）是FTMs中活性最强的成员，对氨基糖苷修饰酶（AMEs）灭活的敏感性最低。因此，本研究旨在评估FTM-A单独或与其他抗生素联合对18株非克隆临床相关MDR革兰氏阳性和革兰氏阴性病原体的抗菌活性。本研究还旨在使用响应面D-最优设计对影响其生产的各种环境因素进行统计优化。结果表明，FTM-A/美罗培南组合显示出最高的协同杀菌活性（61.1%），其次是与头孢噻肟和头孢吡肟的组合（各38.8%）。然而，FTM-A/庆大霉素和FTM-A/多西环素组合在分别66.6%和50%的受试菌株中大多表现为相加作用。对于FTM-A生产优化，使用氨基糖苷生产培养基，其次是酵母提取物-麦芽提取物和M65生产培养基，可实现对细胞生长的最大比活性（μg/mg）。一个由27种不同培养基组成变化组成的D-最优二次模型用于预测FTM-A生产的最佳组成，并进行了实验验证。使用HPLC分析对模型进行实验室验证，与未优化条件相比，其产量提高了10.5倍。该模型表明，初始pH、培养温度和培养时间显著影响FTMs的生产（P值<0.05），然而，测试的碳酸钙范围2-7 gL-1和搅拌速率（100-300 rpm）显示无显著影响（P值>0.05）。总之，D-最优设计产生了一个有效的模型，并在摇瓶水平上优化了FTMs的生产。FTM-A与美罗培南、头孢噻肟、头孢吡肟和庆大霉素的组合大多显示出协同/相加作用，建议进行临床评估。
