Identification of two-component system ArcAB and the universal stress protein E in Pasteurella multocida and their effects on bacterial fitness and pathogenesis

Lv, Qingjie; Shang, Yuyao; Bi, Haixin; Yang, Jie; Lin, Lin; Shi, Congcong; Wang, Mixue; Xie, Rui; Zhu, Zhanwei; Wang, Fei; Hua, Lin; Chen, Huanchun; Wu, Bin; Peng, Zhong

doi:10.1016/j.micinf.2023.105235

Microbes and Infection

2023

DOI: 10.1016/j.micinf.2023.105235

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Identification of two-component system ArcAB and the universal stress protein E in Pasteurella multocida and their effects on bacterial fitness and pathogenesis

Qingjie Lv,

Yuyao Shang,

Haixin Bi

et al.

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2024

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Cited by 2 publications

References 33 publications

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A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

Feng,

Zheng,

et al. 2024

Nat Commun

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The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

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A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

Feng,

Zheng,

et al. 2024

Nat Commun

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The phosphoethanolamine transferase PetL of Pasteurella multocida is associated with colistin resistance

Yang,

Lin,

et al. 2024

Animal Diseases

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The rapid emergence and spread of colistin-resistant gram-negative bacteria has raised worldwide public health concerns, and phosphoethanolamine (PEtn) transferase modification-mediated colistin resistance has been widely documented in multiple gram-negative bacterial species. However, whether such a mechanism exists in the zoonotic pathogen Pasteurella multocida is still unknown. Recently, a novel PEtn transferase, PetL, was identified in P. multocida, but whether it is associated with colistin resistance remains to be elucidated. In this study, we found that PetL in P. multocida (PetLPM) exhibited structural characteristics similar to those of the mobile-colistin-resistant (MCR) protein and the PEtn transferase characterized in Neisseria meningitidis. The transformation of petLPM into E. coli or K. pneumoniae changed the phenotype of several tested strains from colistin sensitive to colistin resistant. Deletion of this gene decreased the colistin minimum inhibitory concentration (MIC) of P. multocida by 64-fold. Our extensive analysis by MALDI-TOF–MS demonstrated that PetLPM participated in the modification of bacterial lipopolysaccharide (LPS)-lipid A. Deletion of petLPM led to an increase in membrane charge but a decrease in cell-surface hydrophobicity and cell permeability in P. multocida. The present study is the first to report the presence of PEtn transferase-mediated colistin resistance in the zoonotic pathogen P. multocida.

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Identification of two-component system ArcAB and the universal stress protein E in Pasteurella multocida and their effects on bacterial fitness and pathogenesis

Cited by 2 publications

References 33 publications

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

The phosphoethanolamine transferase PetL of Pasteurella multocida is associated with colistin resistance

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