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Conjugative transfer of streptococcal prophages harboring antibiotic resistance and virulence genes

The ISME Journal volume 17, pages 1467–1481 (2023)Cite this article

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Abstract

Prophages play important roles in the transduction of various functional traits, including virulence factors, but remain debatable in harboring and transmitting antimicrobial resistance genes (ARGs). Herein we characterize a prevalent family of prophages in Streptococcus, designated SMphages, which harbor twenty-five ARGs that collectively confer resistance to ten antimicrobial classes, including vanG-type vancomycin resistance locus and oxazolidinone resistance gene optrA. SMphages integrate into four chromosome attachment sites by utilizing three types of integration modules and undergo excision in response to phage induction. Moreover, we characterize four subtypes of Alp-related surface proteins within SMphages, the lethal effects of which are extensively validated in cell and animal models. SMphages transfer via high-frequency conjugation that is facilitated by integrative and conjugative elements from either donors or recipients. Our findings explain the widespread of SMphages and the rapid dissemination of ARGs observed in members of the Streptococcus genus.

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Fig. 1: SMphage organization and prophage-host crosstalk inferred by phylogenetic analysis of SMphage and bacterial genomes.
Fig. 2: ARG-carrying fragments accreted within VRs of Clade_Ssu subgroup SMphages.
Fig. 3: Integration and excision of SMphages.
Fig. 4: HGT mechanisms of SMphages.
Fig. 5: Alp-Ps of Clade_Sag subgroup SMphages contributed to bacterial virulence to bacterial host.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2022YFD1800400), the National Natural Science Foundation of China (32172917, 32072915 and 31872517), the Natural Science Foundation of Jiangsu Province (BK20170710 and BK20210402), the Jiangsu Agriculture Science and Technology Innovation Fund (CX(22)3039), the Jiangsu Distinguished Professor Program (060804097), the Distinguished Young Scholars of the National Natural Science Foundation of China (Overseas), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The bioinformatics analyses were supported by the high-performance computing platform of Bioinformatics Center, Nanjing Agricultural University, and a startup award at Nanjing Agricultural University 060804009).

We would like to thank Dr. Zongfu Wu and Jiale Ma from Nanjing Agricultural University for their assistance in the bacterial virulence study, and Dr. Qijing Zhang from Iowa State University for fruitful discussions and manuscript improvement.

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  1. These authors contributed equally: Jinhu Huang, Xingyang Dai, Zuowei Wu.

Authors and Affiliations

  1. MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Jinhu Huang, Xingyang Dai, Junjie Sun, Peizhao Han, Jiaqi Zhao, Xiaoming Wang & Liping Wang

  2. Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA

    Zuowei Wu & Xiao Hu

  3. Ruminant Nutrition and Feed Engineering Technology Research Center, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China

    Yijun Tang, Wanqiu Zhang, Shengyong Mao & Jinxin Liu

  4. Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China

    Yijun Tang, Wanqiu Zhang, Shengyong Mao & Jinxin Liu

  5. Key Lab of Animal Bacteriology, Ministry of Agriculture, OIE Reference Lab for Swine Streptococcosis, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Guangjin Liu

  6. Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China

    Yang Wang

  7. Paul G. Allen School for Global Health, Washington State University, Pullman, WA, 99164, USA

    Douglas R. Call

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Contributions

JH and LW conceived and designed the experiments. JH, ZW, JL, YT, WZ and XH performed bioinformatics analyses. JH, XD, JS, PH and JZ generated strains and plasmids and performed HGT and other experiments. XD, GL and XW performed the cell and animal experiments. JH, XD and ZW wrote the original draft. LW, JL, DRC, YW and SM reviewed and edited the manuscript.

Corresponding authors

Correspondence to Jinxin Liu or Liping Wang.

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Animal experiments were carried out at the Laboratory Animal Center of Nanjing Agricultural University, according to the guidelines of Experimental Animal Management Measures of Jiangsu Province and were approved by the Laboratory Animal Monitoring Committee of Jiangsu Province, China [Permit number: SYXK (Su) 2017-0007].

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Huang, J., Dai, X., Wu, Z. et al. Conjugative transfer of streptococcal prophages harboring antibiotic resistance and virulence genes. ISME J 17, 1467–1481 (2023). https://doi.org/10.1038/s41396-023-01463-4

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