Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics
ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the amin...
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American Society for Microbiology
2014
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oai:doaj.org-article:e75ab41e6d784ecd8f204ed86b0f40192021-11-15T15:45:54ZIdentification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics10.1128/mBio.01827-142150-7511https://doaj.org/article/e75ab41e6d784ecd8f204ed86b0f40192014-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01827-14https://doaj.org/toc/2150-7511ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. IMPORTANCE The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.Stefan DuschaHeithem BoukariDimitri ShcherbakovSumantha SalianSandrina SilvaAnn KendallTakayuki KatoRashid AkbergenovDeborah Perez-FernandezBruno BernetSwapna VaddiPia ThommesJochen SchachtDavid CrichAndrea VasellaErik C. BöttgerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 5 (2014) |
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Microbiology QR1-502 |
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Microbiology QR1-502 Stefan Duscha Heithem Boukari Dimitri Shcherbakov Sumantha Salian Sandrina Silva Ann Kendall Takayuki Kato Rashid Akbergenov Deborah Perez-Fernandez Bruno Bernet Swapna Vaddi Pia Thommes Jochen Schacht David Crich Andrea Vasella Erik C. Böttger Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| description |
ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. IMPORTANCE The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms. |
| format |
article |
| author |
Stefan Duscha Heithem Boukari Dimitri Shcherbakov Sumantha Salian Sandrina Silva Ann Kendall Takayuki Kato Rashid Akbergenov Deborah Perez-Fernandez Bruno Bernet Swapna Vaddi Pia Thommes Jochen Schacht David Crich Andrea Vasella Erik C. Böttger |
| author_facet |
Stefan Duscha Heithem Boukari Dimitri Shcherbakov Sumantha Salian Sandrina Silva Ann Kendall Takayuki Kato Rashid Akbergenov Deborah Perez-Fernandez Bruno Bernet Swapna Vaddi Pia Thommes Jochen Schacht David Crich Andrea Vasella Erik C. Böttger |
| author_sort |
Stefan Duscha |
| title |
Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| title_short |
Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| title_full |
Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| title_fullStr |
Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| title_full_unstemmed |
Identification and Evaluation of Improved 4′-<italic toggle="yes">O</italic>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics |
| title_sort |
identification and evaluation of improved 4′-<italic toggle="yes">o</italic>-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics |
| publisher |
American Society for Microbiology |
| publishDate |
2014 |
| url |
https://doaj.org/article/e75ab41e6d784ecd8f204ed86b0f4019 |
| work_keys_str_mv |
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