Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary
Adam J Plaunt1, Sasha J Rose1, Jeong Yeon Kang1
1Insmed Incorporated, Bridgewater, New Jersey, USA.
Abstract:
Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability 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 in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was 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 vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-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 vitro evaluation 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 vivo efficacy 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.
Insights
A novel lipoglycopeptide therapy shows promise for treating chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients. This new treatment is effective against MRSA in biofilms and inside cells, offering a potential solution for recurrent infections.
Area of Science:
- Microbiology
- Pharmacology
- Drug Delivery
Background:
- Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients are difficult to treat and often recur.
- Standard antibiotic treatments have limited efficacy against protected MRSA forms like biofilms and intracellular bacteria, leading to reduced life expectancy.
Purpose of the Study:
- To develop and evaluate a novel lipoglycopeptide therapy for pulmonary delivery targeting chronic MRSA infections in CF.
- To synthesize next-generation lipoglycopeptides with improved pharmacokinetics and pharmacodynamics for enhanced efficacy.
Main Methods:
- Synthesized a library of vancomycin-modified lipoglycopeptides with varied hydrophobic modifications.
- Evaluated in vitro activity against planktonic, intracellular, and biofilm MRSA, and Gram-positive organisms.
- Assessed in vivo pharmacokinetics via inhalation in rats and in vivo efficacy in a rat model of pulmonary MRSA infection.
Main Results:
- Several synthesized lipoglycopeptides demonstrated 30-60 times greater in vitro potency than vancomycin.
- RV94, a lipoglycopeptide with an inverted amide linker, showed favorable lung residence time and superior in vitro activity, including against intracellular MRSA and biofilms.
- Inhaled nebulized RV94 demonstrated statistically significant and superior in vivo antibacterial activity compared to inhaled vancomycin in a pulmonary MRSA infection model.
Conclusions:
- The novel lipoglycopeptide RV94 exhibits potent in vitro and in vivo activity against MRSA, including challenging forms like biofilms and intracellular bacteria.
- Pulmonary delivery of RV94 represents a promising therapeutic strategy for chronic MRSA lung infections in CF patients, addressing a significant unmet medical need.
