Dynamics of Antibacterial Drone Establishment in Staphylococcus aureus: Unexpected Effects of Antibiotic Resistance Genes

Dhasmana, Neha; Ram, Geeta; McAllister, Kathleen N; Chupalova, Yulia; Lopez, Peter; Ross, Hope F.; Novick, Richard P.

doi:10.1128/mbio.02083-21

mBio

2021

DOI: 10.1128/mbio.02083-21

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Dynamics of Antibacterial Drone Establishment in Staphylococcus aureus: Unexpected Effects of Antibiotic Resistance Genes

Neha Dhasmana

Geeta Ram

Kathleen N McAllister

et al.

Abstract: For a particulate therapeutic agent, such as the ABD, accurate enumeration of particles is critical to enable evaluation of preparative procedures and calculation of therapeutic dosages. It is equally important that a selective marker used for these two purposes be biologically inert.

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Cited by 3 publications

References 31 publications

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CRISPR-Cas System: A New Dawn to Combat Antibiotic Resistance

Rafiq,

Shabbir,

Raza

et al. 2024

BioDrugs

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CRISPR-Cas System: A New Dawn to Combat Antibiotic Resistance

Rafiq,

Shabbir,

Raza

et al. 2024

BioDrugs

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ABD-3, the confluence of powerful antibacterial modalities: ABDs delivering and expressing ls s, the gene encoding lysostaphin

Ram,

Chiu,

Dey

et al. 2024

Antimicrob Agents Chemother

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In response to the antimicrobial resistance crisis, we have developed a powerful and versatile therapeutic platform, the Antibacterial Drone (ABD) system. The ABD consists of a highly mobile staphylococcal pathogenicity island re-purposed to deliver genes encoding antibacterial proteins. The chromosomally located island is induced by a co-resident helper phage, packaged in phage-like particles, and released in very high numbers upon phage-induced lysis. ABD particles specifically adsorb to bacteria causing an infection and deliver their DNA to these bacteria, where the bactericidal cargo genes are expressed, kill the bacteria, and cure the infection. Here, we report a major advance of the system, incorporation of the gene encoding a secreted, bactericidal, species-specific lytic enzyme, lysostsphin. This ABD not only kills the bacterium that has been attacked by the ABD, but also any surrounding bacteria that are sensitive to the lytic enzyme which is released by secretion and by lysis of the doomed cell. So while the killing field is thus expanded, there are no civilian casualties (bacteria that are insensitive to the ABD and its cargo protein(s) are not inadvertently killed). Without amplifying the number of ABD particles (which are not re-packaged), the expression and release of the cargo gene’s product dramatically extend the effective reach of the ABD. A cargo gene that encodes a secreted bactericidal protein also enables the treatment of a mixed bacterial infection in which one of the infecting organisms is insensitive to the ABD delivery system but is sensitive to the ABD’s secreted cargo protein.

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Identification of Therapeutic Targets in an Emerging Gastrointestinal Pathogen Campylobacter ureolyticus and Possible Intervention through Natural Products

et al. 2022

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Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes gastrointestinal infections. Being the most prevalent cause of bacterial enteritis globally, infection by this bacterium is linked with significant morbidity and mortality in children and immunocompromised patients. No information on pan-therapeutic drug targets for this species is available yet. In the current study, a pan-genome analysis was performed on 13 strains of C. ureolyticus to prioritize potent drug targets from the identified core genome. In total, 26 druggable proteins were identified using subtractive genomics. To the best of the authors’ knowledge, this is the first report on the mining of drug targets in C. ureolyticus. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) was selected as a promiscuous pharmacological target for virtual screening of two bacterial-derived natural product libraries, i.e., postbiotics (n = 78) and streptomycin (n = 737) compounds. LpxC inhibitors from the ZINC database (n = 142 compounds) were also studied with reference to LpxC of C. ureolyticus. The top three docked compounds from each library (including ZINC26844580, ZINC13474902, ZINC13474878, Notoginsenoside St-4, Asiaticoside F, Paraherquamide E, Phytoene, Lycopene, and Sparsomycin) were selected based on their binding energies and validated using molecular dynamics simulations. To help identify potential risks associated with the selected compounds, ADMET profiling was also performed and most of the compounds were considered safe. Our findings may serve as baseline information for laboratory studies leading to the discovery of drugs for use against C. ureolyticus infections.

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Dynamics of Antibacterial Drone Establishment in Staphylococcus aureus: Unexpected Effects of Antibiotic Resistance Genes

Abstract: For a particulate therapeutic agent, such as the ABD, accurate enumeration of particles is critical to enable evaluation of preparative procedures and calculation of therapeutic dosages. It is equally important that a selective marker used for these two purposes be biologically inert.

Cited by 3 publications

References 31 publications

CRISPR-Cas System: A New Dawn to Combat Antibiotic Resistance

CRISPR-Cas System: A New Dawn to Combat Antibiotic Resistance

ABD-3, the confluence of powerful antibacterial modalities: ABDs delivering and expressing ls s, the gene encoding lysostaphin

Identification of Therapeutic Targets in an Emerging Gastrointestinal Pathogen Campylobacter ureolyticus and Possible Intervention through Natural Products

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