Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers
Lariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/10/1513 |
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| author | Mohit B. Patel Helena Spikes Robert S. Bailey Thomas Connell Hannah Gill Michael R. Gokel Rebecca Harris Joseph W. Meisel Saeedeh Negin Shanheng Andrew Yin George W. Gokel |
| author_facet | Mohit B. Patel Helena Spikes Robert S. Bailey Thomas Connell Hannah Gill Michael R. Gokel Rebecca Harris Joseph W. Meisel Saeedeh Negin Shanheng Andrew Yin George W. Gokel |
| author_sort | Mohit B. Patel |
| collection | DOAJ |
| description | Lariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of <i>E. coli</i> and <i>Staphylococcus aureus</i> having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against <i>S. aureus</i> 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development. |
| first_indexed | 2024-03-10T21:29:31Z |
| format | Article |
| id | doaj.art-8f3ac2720fb5453f89aef58f557f073e |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T21:29:31Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-8f3ac2720fb5453f89aef58f557f073e2023-11-19T15:26:33ZengMDPI AGAntibiotics2079-63822023-10-011210151310.3390/antibiotics12101513Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat EthersMohit B. Patel0Helena Spikes1Robert S. Bailey2Thomas Connell3Hannah Gill4Michael R. Gokel5Rebecca Harris6Joseph W. Meisel7Saeedeh Negin8Shanheng Andrew Yin9George W. Gokel10Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USADepartment of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USALariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of <i>E. coli</i> and <i>Staphylococcus aureus</i> having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against <i>S. aureus</i> 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.https://www.mdpi.com/2079-6382/12/10/1513adjuvantantibioticantibiotic resistancebacteriacrown ethercytotoxicity |
| spellingShingle | Mohit B. Patel Helena Spikes Robert S. Bailey Thomas Connell Hannah Gill Michael R. Gokel Rebecca Harris Joseph W. Meisel Saeedeh Negin Shanheng Andrew Yin George W. Gokel Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers Antibiotics adjuvant antibiotic antibiotic resistance bacteria crown ether cytotoxicity |
| title | Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers |
| title_full | Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers |
| title_fullStr | Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers |
| title_full_unstemmed | Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers |
| title_short | Antimicrobial and Adjuvant Potencies of Di-<i>n</i>-alkyl Substituted Diazalariat Ethers |
| title_sort | antimicrobial and adjuvant potencies of di i n i alkyl substituted diazalariat ethers |
| topic | adjuvant antibiotic antibiotic resistance bacteria crown ether cytotoxicity |
| url | https://www.mdpi.com/2079-6382/12/10/1513 |
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