Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology , Jinan University , Guangzhou 510632 , China.
Department of Clinical Laboratory , Nanfang Hospital, Southern Medical University , Guangzhou 510632 , China.
J Proteome Res. 2019 Nov 1;18(11):3955-3966. doi: 10.1021/acs.jproteome.9b00410. Epub 2019 Oct 23.
Advancements in studies on the evolutionary mechanisms underlying bacterial antibiotic resistance are unclear. This study aimed to investigate the evolutionary mechanism underlying bacterial antibiotic resistance using isobaric tags for relative and absolute quantitation-based quantitative proteomics along with functional validation. Quantitative analysis revealed 101, 325, and 428 differentially expressed proteins (DEPs) at three drug resistance levels (low-R, 0.2 μg/mL; medium-R, 5 μg/mL; high-R, 15 μg/mL). Continuous adjustment of metabolic patterns to enhance nucleotide synthesis and energy generation may underlie evolution. Indeed, nucleotide levels were elevated and strengthened ciprofloxacin resistance. Quorum sensing (QS) genes were upregulated in the early growth phase, thus potentially improving survival. Further, a thicker cell wall potentially serves as a stronger barrier and reduces drug permeation. The aforementioned three drug resistance levels displayed continuity and differences; the low-resistant level displayed no prominent mechanism; medium, a more focused change in nucleotide metabolism; and high, a thorough evolution to a complete systematic mechanism with higher adenosine 5'-triphosphate levels, serving as a defense mechanism for reducing drug-induced stress. Thus, gradual increments in nucleotide synthesis, energy synthesis, cell wall synthesis, QS, and biofilm formation may direct the evolution of bacterial resistance.
细菌抗生素耐药性进化机制的研究进展尚不清楚。本研究旨在采用基于相对和绝对定量标记的定量蛋白质组学结合功能验证来研究细菌抗生素耐药性的进化机制。定量分析在三个耐药水平（低耐药，0.2μg/ml；中耐药，5μg/ml；高耐药，15μg/ml）下发现了 101、325 和 428 个差异表达蛋白（DEPs）。连续调整代谢模式以增强核苷酸合成和能量生成可能是进化的基础。事实上，核苷酸水平升高并增强了环丙沙星的耐药性。群体感应（QS）基因在早期生长阶段上调，从而提高了生存能力。此外，更厚的细胞壁可能作为更强的屏障，减少药物渗透。上述三种耐药水平表现出连续性和差异；低耐药水平没有明显的机制；中耐药水平更集中于核苷酸代谢的变化；高耐药水平则是全面进化到一个完整的系统机制，具有更高的三磷酸腺苷水平，作为降低药物诱导应激的防御机制。因此，核苷酸合成、能量合成、细胞壁合成、QS 和生物膜形成的逐渐增加可能指导细菌耐药性的进化。
