Abstract
Antibiotic resistance (AMR) has always been a hot topic all over the world and its mechanisms are varied and complicated. Previous evidence revealed the metabolic slowdown in resistant bacteria, suggesting the important role of metabolism in antibiotic resistance. However, the molecular mechanism of reduced metabolism remains poorly understood, which inspires us to explore the global proteome change during antibiotic resistance. Here, the sensitive, cotrimoxazole-resistant, amikacin-resistant, and amikacin/cotrimoxazole -both-resistant KPN clinical isolates were collected and subjected to proteome analysis through liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). A deep coverage of 2,266 proteins were successfully identified and quantified in total, representing the most comprehensive protein quantification data by now. Further bioinformatic analysis showed down-regulation of tricarboxylic acid cycle (TCA) pathway and up-regulation of alcohol metabolic or glutathione metabolism processes, which may contribute to ROS clearance and cell survival, in drug-resistant isolates. These results indicated that metabolic pathway alteration was directly correlated with antibiotic resistance, which could promote the development of antibacterial drugs from “target” to “network.” Moreover, combined with minimum inhibitory concentration (MIC) of cotrimoxazole and amikacin on different KPN isolates, we identified nine proteins, including garK, uxaC, exuT, hpaB, fhuA, KPN_01492, fumA, hisC, and aroE, which might contribute mostly to the survival of KPN under drug pressure. In sum, our findings provided novel, non-antibiotic-based therapeutics against resistant KPN.
Highlights
Antibiotic resistance (AMR) has always been a hot topic all over the world
These results indicated that the alteration of metabolic network was directly correlated with antibiotic resistance, which could promote the development of antibacterial drugs from “target” to “network,” and provided novel, non-antibiotic-based therapeutics against resistant bacteria
The dynamic ranges of protein quantification values in this study spanned over six orders of magnitude (Supplementary Figure 1A), with the most abundant proteins being rpsU, HupA, tufa, etc. (Supplementary Figure 1B). rpsU, known as ribosomal protein S21, was reported to contribute to fitness, stress-tolerance and host interaction (Koomen et al, 2018)
Summary
Antibiotic resistance (AMR) has always been a hot topic all over the world. The report released by World Health Organization (WHO) revealed that this serious threat is happening in every region of the world and has the potential to affect anyone, of any age, in any country (World Health Organization [WHO], 2014). Mechanistic studies demonstrated that glyoxylate could induce phenotypic resistance of bacteria by inhibiting cellular respiration with acetyl-coenzyme A diversion through the glyoxylate shunt (Meylan et al, 2017) Another empirical study showed that aminoglycosides, such as glucose, mannitol, fructose, and pyruvic acid, improved the sensitivity of Ataphylococcus aureus and Escherichia coli to gentamicin by promoting glycolysis metabolic pathway (Allison et al, 2011). Bai’ group found that the protein aggresome, whose formation is promoted by decreased cellular ATP level, was critical for AMR (Pu et al, 2019; Jing et al, 2020; Jin et al, 2021). The specific metabolism-related protein profiles of resistant bacteria are still poorly understood
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