Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA.
Sci Rep. 2021 Jun 24;11(1):13230. doi: 10.1038/s41598-021-92718-7.
Colistin resistance is complex and multifactorial. DbcA is an inner membrane protein belonging to the DedA superfamily required for maintaining extreme colistin resistance of Burkholderia thailandensis. The molecular mechanisms behind this remain unclear. Here, we report that ∆dbcA displays alkaline pH/bicarbonate sensitivity and propose a role of DbcA in extreme colistin resistance of B. thailandensis by maintaining cytoplasmic pH homeostasis. We found that alkaline pH or presence of sodium bicarbonate displays a synergistic effect with colistin against not only extremely colistin resistant species like B. thailandensis and Serratia marcescens, but also a majority of Gram-negative and Gram-positive bacteria tested, suggesting a link between cytoplasmic pH homeostasis and colistin resistance across species. We found that lowering the level of oxygen in the growth media or supplementation of fermentable sugars such as glucose not only alleviated alkaline pH stress, but also increased colistin resistance in most bacteria tested, likely by avoiding cytoplasmic alkalinization. Our observations suggest a previously unreported link between pH, oxygen, and colistin resistance. We propose that maintaining optimal cytoplasmic pH is required for colistin resistance in a majority of bacterial species, consistent with the emerging link between cytoplasmic pH homeostasis and antibiotic resistance.
多粘菌素耐药性是复杂的和多因素的。DbcA 是一种内膜蛋白，属于 DedA 超家族，是维持伯克霍尔德菌极端多粘菌素耐药性所必需的。其背后的分子机制尚不清楚。在这里，我们报告 ∆dbcA 显示碱性 pH/碳酸氢盐敏感性，并提出 DbcA 通过维持细胞质 pH 稳态在伯克霍尔德菌极端多粘菌素耐药性中的作用。我们发现碱性 pH 或存在碳酸氢钠对不仅是像泰国伯克霍尔德菌和粘质沙雷氏菌这样的极端多粘菌素耐药物种，而且对大多数革兰氏阴性和革兰氏阳性细菌都显示出协同作用，这表明细胞质 pH 稳态和多粘菌素耐药性之间存在物种间的联系。我们发现降低生长培养基中的氧水平或补充可发酵糖（如葡萄糖）不仅缓解了碱性 pH 应激，而且增加了大多数测试细菌的多粘菌素耐药性，这可能是通过避免细胞质碱化来实现的。我们的观察结果表明 pH、氧和多粘菌素耐药性之间存在以前未报道的联系。我们提出，维持最佳细胞质 pH 是大多数细菌多粘菌素耐药性所必需的，这与细胞质 pH 稳态和抗生素耐药性之间的新兴联系一致。
