Schwieters Andrew, Cole Allysa L, Rego Emily, Gao Chengyu, Kebriaei Razieh, Wysocki Vicki H, Gunn John S, Ahmer Brian M M
Department of Microbiology, The Ohio State University, Columbus, Ohio, USA.
Infectious Diseases Institute, The Ohio State University, Columbus, Ohio, USA.
J Bacteriol. 2025 Jan 31;207(1):e0048024. doi: 10.1128/jb.00480-24. Epub 2024 Dec 27.
The ability to treat infections is threatened by the rapid emergence of antibiotic resistance among pathogenic microbes. Therefore, new antimicrobials are needed. Here we evaluate mannitol-1-phosphate 5-dehydrogenase (MtlD) as a potential new drug target. In many bacteria, mannitol is transported into the cell and phosphorylated by MtlA, the EIICBA component of a phosphoenolpyruvate-dependent sugar phosphotransferase system. MtlD catalyzes the conversion of mannitol-1-phosphate (Mtl-1P) to fructose-6-phosphate, which enters the glycolytic pathway. Mutants lacking are sensitive to mannitol due to accumulation of Mtl-1P. Here, we constructed mutants in four different bacterial species (, five serovars of , and three strains of ), confirming and quantifying their mannitol sensitivity. The quantification of mannitol sensitivity was complicated by an inoculum effect and a resumption of growth following mannitol intoxication. The rate of resumption at different mannitol concentrations and cell population densities is fairly constant and reveals what is likely an intoxication processing rate. Provision of mannitol in drinking water, or by intraperitoneal injection, dramatically attenuates infection of a serovar Typhimurium mutant in mouse models of both gastroenteritis and systemic infection. Using CC003/Unc mice, we find that a mutant of serovar Typhi is also attenuated by provision of mannitol in drinking water. Therefore, we postulate that MtlD could be a valuable new therapeutic target.
The ability to treat infections is threatened by the rapid emergence of antibiotic resistance. Mannitol is a polyol used in human medicine and the food industry. During catabolism of mannitol, many bacteria transport mannitol across the inner membrane forming the toxic intermediate mannitol-1-phosphate (Mtl-1P). Mtl-1P must be processed by mannitol dehydrogenase (MtlD) or it accumulates intracellularly, causing growth attenuation. We test and confirm here that mutants of (including UPEC, and EHEC), (including serovars Typhi, and Paratyphi A, B, and C), , and experience mannitol sensitivity . Furthermore, providing mannitol in drinking water can alleviate both gastrointestinal and systemic infections in mice. This suggests that inhibition of MtlD could be a viable antimicrobial strategy.
致病性微生物中抗生素耐药性的迅速出现威胁着治疗感染的能力。因此，需要新的抗菌药物。在此，我们评估了磷酸甘露醇-1-脱氢酶（MtlD）作为一种潜在的新药物靶点。在许多细菌中，甘露醇被转运到细胞内，并由磷酸烯醇丙酮酸依赖性糖磷酸转移酶系统的EIICBA组分MtlA磷酸化。MtlD催化磷酸甘露醇-1-磷酸（Mtl-1P）转化为6-磷酸果糖，后者进入糖酵解途径。缺乏该酶的突变体由于Mtl-1P的积累而对甘露醇敏感。在此，我们在四种不同的细菌物种（大肠杆菌、鼠伤寒沙门氏菌的五个血清型以及金黄色葡萄球菌的三个菌株）中构建了突变体，证实并量化了它们对甘露醇的敏感性。甘露醇敏感性的量化因接种效应和甘露醇中毒后生长的恢复而变得复杂。在不同甘露醇浓度和细胞群体密度下的恢复速率相当恒定，揭示了可能的中毒处理速率。在饮用水中提供甘露醇，或通过腹腔注射，可显著减轻鼠伤寒沙门氏菌突变体在肠胃炎和全身感染小鼠模型中的感染。使用CC003/Unc小鼠，我们发现伤寒沙门氏菌血清型的突变体在饮用水中提供甘露醇时也会减弱。因此，我们推测MtlD可能是一个有价值的新治疗靶点。
治疗感染的能力受到抗生素耐药性迅速出现的威胁。甘露醇是一种用于人类医学和食品工业的多元醇。在甘露醇的分解代谢过程中，许多细菌将甘露醇转运穿过内膜，形成有毒中间体磷酸甘露醇-1-磷酸（Mtl-1P）。Mtl-1P必须由甘露醇脱氢酶（MtlD）处理，否则会在细胞内积累，导致生长减弱。我们在此测试并证实，大肠杆菌（包括UPEC和EHEC）、沙门氏菌（包括伤寒、甲型副伤寒、乙型副伤寒和丙型副伤寒血清型）、金黄色葡萄球菌和肺炎克雷伯菌的突变体对甘露醇敏感。此外，在饮用水中提供甘露醇可以减轻小鼠的胃肠道和全身感染。这表明抑制MtlD可能是一种可行的抗菌策略。
