Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner

Gopinath, Smita; Kim, Myoungjoo V.; Rakib, Tasfia; Wong, Patrick; Zandt, Michael van; Barry, Natasha A.; Kaisho, Tsuneyasu; Goodman, Andrew L.; Iwasaki, Akiko

doi:10.1038/s41564-018-0138-2

Cited by 91 publications

(94 citation statements)

References 55 publications

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“…There has been a growing body of evidence that antibiotics can have a wide range of effects on the host (26). One study of particular note determined that aminoglycoside antibiotics are capable of altering the innate immune response in mice, which resulted in antiviral activity against both DNA and RNA viruses (19). They also found that these antibiotics function in a microbiota-independent manner (19), similar to our observations.…”

Section: Discussionsupporting

confidence: 85%

“…Our group and others have used antibiotics to deplete the host microbiota to study virus-host-microbiota interactions (6,(11)(12)(13)(14). However, antibiotics can have microbiota-independent effects, and alter host metabolic pathways, gene expression profiles, and immune cell function (15)(16)(17)(18)(19). Specifically, antibiotics can alter the host interferon response (19), alter immune cell homing to intestinal tissues (20,21), and can have noncanonical effects on viruses, such as altering plaque size or exacerbating certain viral infections (15,22).…”

Section: Introductionmentioning

confidence: 99%

“…However, antibiotics can have microbiota-independent effects, and alter host metabolic pathways, gene expression profiles, and immune cell function (15)(16)(17)(18)(19). Specifically, antibiotics can alter the host interferon response (19), alter immune cell homing to intestinal tissues (20,21), and can have noncanonical effects on viruses, such as altering plaque size or exacerbating certain viral infections (15,22). Intriguingly, it has been known for over 40 years that certain antibiotics have antiviral properties (23).…”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, it has been known for over 40 years that certain antibiotics have antiviral properties (23). Recently, Gopinath et al demonstrated that aminoglycosides confer antiviral resistance in vivo to a variety of DNA and RNA viruses by altering the host immune response (19). Other antibiotics that have antiviral properties include macrolides (enterovirus A71) (24) and tetracyclines (respiratory syncytial virus) (25).…”

Section: Introductionmentioning

confidence: 99%

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Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Acevedo

Pfeiffer²

2020

Preprint

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Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown that bacteria promote oral infection with a variety of enteric viruses. However, it is unknown whether antibiotics have microbiota-independent antiviral effects for enteric viruses or whether antibiotics influence extra-intestinal, systemic infection. Here, we examined the effects of antibiotics on systemic enteric virus infection by performing intraperitoneal injections of either coxsackievirus B3 (CVB3) or poliovirus followed by quantification of viral titers. We found that antibiotic treatment reduced systemic infection for both viruses. Interestingly, antibiotics reduced CVB3 titers in germ-free mice, suggesting that antibiotic treatment alters CVB3 infection through a microbiota-independent mechanism. Overall, these data provide further evidence that antibiotics can have noncanonical effects on viral infection.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Acevedo

Pfeiffer²

2020

Preprint

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“…Moreover, it is relatively difficult to achieve micromolar EC50 in vivo. For example, aminoglycoside antibiotics, kasugamycin and neomycin were successfully tested against ZIKV, FLUAV, and HSV-2 infections in mice (Gopinath et al, 2018). Polyether antibiotic salinomycin also showed anti-FLUAV effect in mice (Jang et al, 2018).…”

Section: Evaluation Of Bsaas In Animal Modelsmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

198

108

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# Contributed equally J o u r n a l P r e -p r o o f Highlights  We reviewed discovery and development process of broad-spectrum antiviral agents.  We summarized the information on 119 safe-in-man agents in freely accessible database.  Further studies will increase the number of broad-spectrum antivirals, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and reemerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. J o u r n a l P r e -p r o o f 2015). Antiviral drugs and vaccines are used to fight viral infections in human (De Clercq and Li, 2016; Marston et al., 2014). Previously, there has been a focus on "one drug, one virus" dogma, which relied on targeting virus-specific factors. A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015; de Clercq and Montgomery, 1983; Debing et al., 2015; Ianevski et al., 2019; Rada and Dragun, 1977; Sidwell et al., 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al., 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology. Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018; Pushpakom et al., 2019). This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in pre-clinical (animal model) and early clinical developmental phases (phase 0, I and IIa) are already available (Figure 1). Therefore, repositioning of launched or even failed drugs to viral diseases provides unique translational opportunities, includi...

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Metabolic engineering of a robust Escherichia coli strain with a dual protection system

Peng

et al. 2019

Biotech & Bioengineering

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Considerable attention has been given to the development of robust fermentation processes, but microbial contamination and phage infection remain deadly threats that need to be addressed. In this study, a robust Escherichia coli BL21(DE3) strain was successfully constructed by simultaneously introducing a nitrogen and phosphorus (N&P) system in combination with a CRISPR/Cas9 system. The N&P metabolic pathways were able to express formamidase and phosphite dehydrogenase in the host cell, thus enabled cell growth in auxotrophic 3-(N-morpholino) propanesulfonic acid medium with formamide and phosphite as nitrogen and phosphorus sources, respectively. N&P metabolic pathways also allowed efficient expression of heterologous proteins, such as green fluorescent protein (GFP) and chitinase, while contaminating bacteria or yeast species could hardly survive in this medium. The host strain was further engineered by exploiting the CRISPR/Cas9 system to enhance the resistance against phage attack. The resultant strain was able to grow in the presence of T7 phage at a concentration of up to 2 × 10 7 plaqueforming units/ml and produce GFP with a yield of up to 30 μg/10 9 colony-forming units, exhibiting significant advantages over conventional engineered E. coli. This newly engineered, robust E. coli BL21(DE3) strain therefore shows great potential for future applications in industrial fermentation. K E Y W O R D Santimicrobial, anti-phage, CRISPR/Cas9 system, Escherichia coli, N&P pathway

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Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner

Cited by 91 publications

References 55 publications

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Discovery and development of safe-in-man broad-spectrum antiviral agents

Metabolic engineering of a robust Escherichia coli strain with a dual protection system

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