Potential Role of Lysine Acetylation in Antibiotic Resistance of Escherichia coli

Fang, Zuye; Lai, Fubin; Cao, Kun; Zhang, Ziyuan; Cao, Linlin; Liu, Shiqin; Duan, Yufeng; Yin, Xinhua; Ge, Ruiguang; He, Qing‐Yu; Sun, Xia

doi:10.1128/msystems.00649-22

Cited by 14 publications

(10 citation statements)

References 60 publications

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“…The pykF was up-regulated by 1.35 log2 (FC), while the pykA was down-regulated by 1.06 log2 (FC). The studies have reported that pykF is a key upstream kinase to catalyze phosphoenolpyruvate (PEP) producing ATP and promoting energy metabolism causing the sensitivity of drug-resistant strains (Zuye et al 2022 ). Abdelhamid et al ( 2019 ) have demonstrated that pykA plays the dominant role in glycolysis, which is relevant for Pseudomonas aeruginosa virulence, and it is able to influence bacterial pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analyses of Vibrio parahaemolyticus under the phenyllactic acid stress

Lin,

Fang,

Liu

et al. 2024

Appl Microbiol Biotechnol

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Phenyllactic acid (PLA) generally recognized as a natural organic acid shows against Vibrio parahaemolyticus activity. In this study, V. parahaemolyticus ATCC17802 (Vp17802) was cultured under the stress of 1/2MIC PLA, and then the antibacterial mechanisms were explored via transcriptomics. The minimum inhibitory concentration (MIC) of PLA against Vp17802 was 3.2 mg/mL, and the time-kill analysis resulted that Vp17802 was inhibited. PLA was able to destroy the bacterial membrane, leading to the leakage of intracellular substances and decline of ATP levels. The RNA-sequencing analysis results indicated that 1616 significantly differentially expressed genes were identified, among which 190 were up-regulated and 1426 were down-regulated. Down-regulation of the icd2 gene in the TCA cycle mediates blockage of tyrosine metabolic, arginine biosynthesis, and oxidative phosphorylation, causing insufficient energy supply of Vp17802. Moreover, PLA could cause amino acids, metal ions, and phosphate transporters to be blocked, affecting the acquisition of nutrients. The treatment by PLA altered the expression of genes encoding functions involved in quorum sensing, flagellar assembly, and cell chemotaxis pathway, which may be interfering with the biofilm formation in Vp17802, reducing cell motility. Overall, 1.6 mg/mL PLA inhibited the growth of Vp17802 by disrupting to uptake of nutrients, cell metabolism, and the formation of biofilms. The results suggested a new direction for exploring the activity of PLA against Vp17802 and provided a theoretical basis for bacterial pathogen control in the food industry. Key points •RNA sequencing was carried out to indicate the antibacterial mechanism of Vp17802. •The icd2 gene in the TCA cycle mediates blockage of metabolic of Vp17802. •The biofilm formation has interfered with 1.6 mg/mL PLA, which could reduce cell motility and virulence. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analyses of Vibrio parahaemolyticus under the phenyllactic acid stress

Lin,

Fang,

Liu

et al. 2024

Appl Microbiol Biotechnol

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“…Protein acetylation in bacteria may serve many functions, including regulation of central metabolism, growth control, virulence, and biofilm formation [ 1 , 46 , 54 , 55 , 56 , 57 ]. On the global level, acetylation may increase stress resistance [ 42 , 58 ], prevent excessive carbon flux, or serve as a storage mechanism for carbon subunits in the cell [ 9 ]. Acetylation may also protect proteins against irreversible detrimental modifications such as carbonylation or glycation, since all these modifications may occur on the lysine residue [ 9 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies indicate that protein aggregation and acetylation may be responsible for antibiotic resistance or tolerance in E. coli and other Gram-negative bacteria [ 11 , 29 , 30 , 40 , 41 , 42 ]. One example is the correlation between the aggregation of endogenous E. coli proteins and persisters.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Nε-Lysine Acetylation on the Formation of Protein Aggregates and Antibiotic Persistence in E. coli

Stojowska-Swędrzyńska,

Kuczyńska-Wiśnik,

Laskowska

2024

Molecules

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Numerous studies indicate that reversible Nε-lysine acetylation in bacteria may play a key role in the regulation of metabolic processes, transcription and translation, biofilm formation, virulence, and drug resistance. Using appropriate mutant strains deficient in non-enzymatic acetylation and enzymatic acetylation or deacetylation pathways, we investigated the influence of protein acetylation on cell viability, protein aggregation, and persister formation in Escherichia coli. Lysine acetylation was found to increase protein aggregation and cell viability under the late stationary phase. Moreover, increased lysine acetylation stimulated the formation of persisters. These results suggest that acetylation-dependent aggregation may improve the survival of bacteria under adverse conditions (such as the late stationary phase) and during antibiotic treatment. Further experiments revealed that acetylation-favorable conditions may increase persister formation in Klebsiella pneumoniae clinical isolate. However, the exact mechanisms underlying the relationship between acetylation and persistence in this pathogen remain to be elucidated.

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“…Drug resistance of A. fumigatus can be caused by various mechanisms, including intrinsic aberrant gene expression and external environment effectors ( 23 ). Drug resistance is significantly influenced by acetylation and deacetylation ( 24 ), phosphorylation and dephosphorylation ( 25 ), succinylation and desuccinylation ( 26 ), and glycosylation and deglycosylation ( 27 ). Lysine succinylation is a newly identified protein PTM that is vital in cellular physiology.…”

Section: Introductionmentioning

confidence: 99%

Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection

Chen

Meng

et al. 2023

Front. Immunol.

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Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections.

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Potential Role of Lysine Acetylation in Antibiotic Resistance of Escherichia coli

Abstract: The misuse of antibiotics has resulted in the emergence of many antibiotic-resistant strains which seriously threaten human health. Protein post-translational modifications, especially acetylation, tightly control bacterial metabolism.

Cited by 14 publications

References 60 publications

Transcriptomic analyses of Vibrio parahaemolyticus under the phenyllactic acid stress

Transcriptomic analyses of Vibrio parahaemolyticus under the phenyllactic acid stress

Influence of Nε-Lysine Acetylation on the Formation of Protein Aggregates and Antibiotic Persistence in E. coli

Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection

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