| Autor: |
Plaunt, Adam J., Rose, Sasha J., Kang, Jeong Yeon, Chen, Kuan-Ju, LaSala, Daniel, Heckler, Ryan P., Dorfman, Arielle, Smith, Barrett T., Chun, Donald, Viramontes, Veronica, Macaluso, Antonio, Li, Zhili, Zhou, Yuchen, Mark, Lilly, Basso, Jessica, Leifer, Franziska G., Corboz, Michel R., Chapman, Richard W., Cipolla, David, Perkins, Walter R., Malinin, Vladimir S., Konicek, Donna M. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; May 2021, Vol. 1 Issue: 1 |
| Abstrakt: |
Chronic pulmonary MRSA disease in cystic fibrosis (CF) has a high probably of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA but also against protected colonies of MRSA both in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides were synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitrowith several compounds being 30-60 times more potent than vancomycin. Several compounds were advanced into in vivonose-only inhalation PK evaluations in rats where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitroevaluation of RV94 showed superior activity to vancomycin against an expanded panel of gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivoefficacy of inhaled nebulized RV94 in a 48-h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin. |
| Databáze: |
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