Abstract
ABSTRACTChronic 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.
Highlights
There are currently no approved therapies in the United States to treat chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with cystic fibrosis (CF), a disease that affects approximately 25% of patients and has been associated with shortened life expectancy [1, 2]
MRSA infection in CF patients that demonstrates high potency against planktonic, biofilm, and intracellular MRSA, the latter two of which have been linked to clinical relapse after conventional therapy with front-line treatment options such as intravenous vancomycin [16, 17]
The RV compound library of semisynthetic lipoglycopeptide derivatives was developed by modifying vancomycin at its vancosamine position using several different carbonyl linking configurations to extend various acyl chain lengths (Table 1)
Summary
There are currently no approved therapies in the United States to treat chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with cystic fibrosis (CF), a disease that affects approximately 25% of patients and has been associated with shortened life expectancy [1, 2]. Chemical design approaches implemented to conserve high potencies of lipoglycopeptides and efficient membrane permeability often run counter to approaches to improve in vivo clearance An example of this was highlighted during development of telavancin, where the synthetic intermediate N-decylaminoethylvancomycin, a molecule that we have recapitulated and refer to as RV40 demonstrated highly potent in vitro activity but was found to accumulate in off-target tissues when administered parenterally to rodents [15]. This design platform enabled interrogation of a unique path to optimize the physiochemical properties of the molecule, resulting in improved in vivo PK relative to inhaled telavancin while concurrently conserving superior activity in comparison to vancomycin for the treatment of planktonic and protected populations of MRSA
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