Tanzawaic Acids, a Chemically Novel Set of Bacterial Conjugation Inhibitors

Getino, María; Fernández-López, Raúl; Palencia-Gándara, Carolina; Campos-Gómez, Javier; López, José María Sánchez; Martínez, Marta; Fernández, Antonio; Cruz, Fernando de la

doi:10.1371/journal.pone.0148098

Cited by 42 publications

(35 citation statements)

References 43 publications

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“…Identification of antiplasmid compounds has been slow, in large part due to dependence upon laborious plating experiments, which are not amenable to medium-/ high-throughput screening. Apart from one screening system for conjugation inhibitors (48,92,93), most studies of antiplasmid compounds have used classical conjugation experiments. We developed and applied a fluorescence-based assay to monitor the movement of globally prevalent plasmids associated with human infections in two different Gram-negative species with plasmids carrying ESBL or carbapenemase genes.…”

Section: Discussionmentioning

confidence: 99%

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

Buckner

Ciusa

Meek

et al. 2020

mBio

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Antimicrobial-resistant (AMR) infections pose a serious risk to human and animal health. A major factor contributing to this global crisis is the sharing of resistance genes between different bacteria via plasmids. The WHO lists Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, producing extended-spectrum β-lactamases (ESBL) and carbapenemases as “critical” priorities for new drug development. These resistance genes are most often shared via plasmid transfer. However, finding methods to prevent resistance gene sharing has been hampered by the lack of screening systems for medium-/high-throughput approaches. Here, we have used an ESBL-producing plasmid, pCT, and a carbapenemase-producing plasmid, pKpQIL, in two different Gram-negative bacteria, E. coli and K. pneumoniae. Using these critical resistance-pathogen combinations, we developed an assay using fluorescent proteins, flow cytometry, and confocal microscopy to assess plasmid transmission inhibition within bacterial populations in a medium-throughput manner. Three compounds with some reports of antiplasmid properties were tested; chlorpromazine reduced transmission of both plasmids and linoleic acid reduced transmission of pCT. We screened the Prestwick library of over 1,200 FDA-approved drugs/compounds. From this, we found two nucleoside analogue drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduced plasmid transmission (AZT, e.g., at 0.25 μg/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plasmid transmission was reduced by concentrations of the drugs which are below peak serum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids. IMPORTANCE More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-based system to search for drugs that will stop bacteria from sharing resistance genes. We uncovered a new role for two drugs used to treat HIV and show that they are able to prevent the sharing of two different types of resistance genes in two unique bacterial strains. This work lays the foundation for future work to reduce the prevalence of resistant infections.

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Section: Discussionmentioning

confidence: 99%

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

Buckner

Ciusa

Meek

et al. 2020

mBio

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“…These target the ATPase associated with the T4SS (Ripoll‐Rozada et al, ). Tanzawaic acids show particular promise having relatively broad host‐range against different types of plasmid conjugation while being relatively nontoxic (to bacteria, fungi, and human cells; Getino et al, ). Finally, compounds that target the expression or maintenance of the conjugative element are possible.…”

Section: Inhibiting the Plasmidmentioning

confidence: 99%

Inhibiting conjugation as a tool in the fight against antibiotic resistance

Palm

Warringer

et al. 2018

Drug Development Research

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Antibiotic resistance, especially in gram‐negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid‐encoded conjugation system and the host‐encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.

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“…It exhibited significant cytotoxicity with mean IC 50 values ranging from 0.28 to 6 μM in 14 different solid tumors (36 tumor cell lines) [ 133 , 134 ]. Penicillium fungi are also a good source of tanzawaic acid polyketides, which exhibit antibiotic resistance [ 135 ], as well as anti-inflammatory [ 136 ] and cytotoxic activities. Tanzawaic acid P ( 201 ), isolated from a marine-derived fungus, Penicillium sp.…”

Section: Polyketidesmentioning

confidence: 99%

Marine-Derived Penicillium Species as Producers of Cytotoxic Metabolites

Liu

Song

et al. 2017

Marine Drugs

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Since the discovery of penicillin, Penicillium has become one of the most attractive fungal genera for the production of bioactive molecules. Marine-derived Penicillium has provided numerous excellent pharmaceutical leads over the past decades. In this review, we focused on the cytotoxic metabolites * (* Cytotoxic potency was referred to five different levels in this review, extraordinary (IC50/LD50: <1 μM or 0.5 μg/mL); significant (IC50/LD50: 1~10 μM or 0.5~5 μg/mL); moderate (IC50/LD50: 10~30 μM or 5~15 μg/mL); mild (IC50/LD50: 30~50 μM or 15~25 μg/mL); weak (IC50/LD50: 50~100 μM or 25~50 μg/mL). The comparative potencies of positive controls were referred when they were available). produced by marine-derived Penicillium species, and on their cytotoxicity mechanisms, biosyntheses, and chemical syntheses.

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Tanzawaic Acids, a Chemically Novel Set of Bacterial Conjugation Inhibitors

Cited by 42 publications

References 43 publications

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

Inhibiting conjugation as a tool in the fight against antibiotic resistance

Marine-Derived Penicillium Species as Producers of Cytotoxic Metabolites

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