Microbial Genomics as a Catalyst for Targeted Antivirulence Therapeutics

doi:10.3389/fmed.2021.641260

. 2021 Apr 13:8:641260.

doi: 10.3389/fmed.2021.641260. eCollection 2021.

Microbial Genomics as a Catalyst for Targeted Antivirulence Therapeutics

Vitali Sintchenko^{1

2

3}, Verlaine Timms², Eby Sim³, Rebecca Rockett^{1

2}, Nathan Bachmann², Matthew O'Sullivan^{1

2

3}, Ben Marais^{1

4}

Affiliations

¹ Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia.
² Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Westmead, NSW, Australia.
³ Centre for Infectious Diseases and Microbiology Laboratory Services, NSW Health Pathology-Institute of Clinical Pathology and Medical Research, Westmead, NSW, Australia.
⁴ Children's Hospital at Westmead, Westmead, NSW, Australia.

PMID: 33928102
PMCID: PMC8076527
DOI: 10.3389/fmed.2021.641260

Microbial Genomics as a Catalyst for Targeted Antivirulence Therapeutics

Vitali Sintchenko et al. Front Med (Lausanne). 2021.

. 2021 Apr 13:8:641260.

doi: 10.3389/fmed.2021.641260. eCollection 2021.

Authors

Vitali Sintchenko^{1

2

3}, Verlaine Timms², Eby Sim³, Rebecca Rockett^{1

2}, Nathan Bachmann², Matthew O'Sullivan^{1

2

3}, Ben Marais^{1

4}

Affiliations

¹ Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia.
² Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Westmead, NSW, Australia.
³ Centre for Infectious Diseases and Microbiology Laboratory Services, NSW Health Pathology-Institute of Clinical Pathology and Medical Research, Westmead, NSW, Australia.
⁴ Children's Hospital at Westmead, Westmead, NSW, Australia.

PMID: 33928102
PMCID: PMC8076527
DOI: 10.3389/fmed.2021.641260

Abstract

Virulence arresting drugs (VAD) are an expanding class of antimicrobial treatment that act to "disarm" rather than kill bacteria. Despite an increasing number of VAD being registered for clinical use, uptake is hampered by the lack of methods that can identify patients who are most likely to benefit from these new agents. The application of pathogen genomics can facilitate the rational utilization of advanced therapeutics for infectious diseases. The development of genomic assessment of VAD targets is essential to support the early stages of VAD diffusion into infectious disease management. Genomic identification and characterization of VAD targets in clinical isolates can augment antimicrobial stewardship and pharmacovigilance. Personalized genomics guided use of VAD will provide crucial policy guidance to regulating agencies, assist hospitals to optimize the use of these expensive medicines and create market opportunities for biotech companies and diagnostic laboratories.

Keywords: antibacterial treatment; antimicrobial stewardship; genome sequence analysis; surveillance; virulence.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**Figure 1**
Overview of the competitive landscape for virulence arresting drugs (VAD).

**Figure 2**
Examples of variation in virulence genes and proteins affecting VAD targets. The size of letters representing nucleotides (DNA) or amino acids (Protein) reflects their relative frequency in individual positions in the VAD target gene. Only 6% of *Streptococcus pneumoniae comB* gene (75-bp of 1,326-bp gene) and 2% of *Clostridium difficile tcdB* gene (90-bp of 7,101-bp gene) are shown; multiple sequence variations with amino acid relevance are present. Amino acids are colored according to their chemical properties: polar amino acids are green, basic blue, and hydrophobic are black. The height of the y-axis indicates the maximum entropy for the given sequence type. Prepared using Weblogo (www.weblogo.berkeley.edu).

**Figure 3**
Proposed pathway for using genomic profiling for VAD selection.

See this image and copyright information in PMC

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References

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[1] Leguia M, Vila-Sanjurjo A, Chain PSG, Maljkovic-Berry I, Jarman RG, Pollett S. Precision medicine and precision public health in the era of pathogen next generation sequencing. J Infect Dis. (2020) 21 (Suppl. 3):S289–S91. 10.1093/infdis/jiz424 - DOI - PMC - PubMed

[2] Leguia M, Vila-Sanjurjo A, Chain PSG, Maljkovic-Berry I, Jarman RG, Pollett S. Precision medicine and precision public health in the era of pathogen next generation sequencing. J Infect Dis. (2020) 21 (Suppl. 3):S289–S91. 10.1093/infdis/jiz424 - DOI - PMC - PubMed

[3] Faulkner E, Spinner DS, Ringo M, Carroll M. Are global health systems ready for transformative therapies? Value Health. (2019) 22:627–41. 10.1016/j.jval.2019.04.1911 - DOI - PubMed

[4] Faulkner E, Spinner DS, Ringo M, Carroll M. Are global health systems ready for transformative therapies? Value Health. (2019) 22:627–41. 10.1016/j.jval.2019.04.1911 - DOI - PubMed

[5] Kim J, Hu C, El Achkar CM, Black LE, Douville J, Larson A, et al. . Patient-customized oligonucleotide therapy for a rare genetic disease. New Engl J Med. (2019) 381:1644–52. 10.1056/NEJMoa1813279 - DOI - PMC - PubMed

[6] Kim J, Hu C, El Achkar CM, Black LE, Douville J, Larson A, et al. . Patient-customized oligonucleotide therapy for a rare genetic disease. New Engl J Med. (2019) 381:1644–52. 10.1056/NEJMoa1813279 - DOI - PMC - PubMed

[7] Dickey SW, Cheung GYC, Otto M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov. (2017) 16:457–71. 10.1038/nrd.2017.23 - DOI - PMC - PubMed

[8] Dickey SW, Cheung GYC, Otto M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov. (2017) 16:457–71. 10.1038/nrd.2017.23 - DOI - PMC - PubMed

[9] Allen RC, Popat R, Diggle SP, Brown SP. Targeting virulence: can we make evolution-proof drugs? Nat Rev Microbiol. (2014) 12:300–8. 10.1038/nrmicro3232 - DOI - PubMed

[10] Allen RC, Popat R, Diggle SP, Brown SP. Targeting virulence: can we make evolution-proof drugs? Nat Rev Microbiol. (2014) 12:300–8. 10.1038/nrmicro3232 - DOI - PubMed

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Microbial Genomics as a Catalyst for Targeted Antivirulence Therapeutics

Affiliations

Microbial Genomics as a Catalyst for Targeted Antivirulence Therapeutics

Authors

Affiliations

Abstract

Conflict of interest statement

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