Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections

Abstract

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 vitro with several compounds being 30-60 times more potent than vancomycin. Several 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.

Design, synthesis, biological evaluation and molecular docking studies of novel pleuromutilin derivatives containing nitrogen heterocycle and alkylamine groups

“…25 μg/mL). Therefore, we hypothesised that the longer side chain of the introduced secondary amine might yield the poorer antibacterial activity, which was consistent with previously reported 18 . When the terminal methyl group in compound 11 was replaced by hydroxyl, compound 13 (MIC = 0.0625 μg/mL) was obtained.…”

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

“…Representative amide 40 ( Figure 10 ) was selected for extensive investigation due to (1) its potent in vitro activity against target bacteria MRSA (MIC = 0.015 μg/mL), S. pneumoniae (MIC = 0.008 μg/mL), C. difficile (MIC = 0.015–0.06 μg/mL), VanA-type VRE (MIC = 0.03–2 μg/mL), and VanB-type VRE (MIC = 0.03 μg/mL) ( Table 1 ) and (2) its prolonged exposure time after inhalation in rats, with a half-life of 108 h, minimal conversion to the hydrolysis product, and minimal systemic toxicity. 210 Amide 40 was also found to have enhanced anti-biofilm activity compared to vancomycin. Furthermore, nebulized 40 was assessed in an in vivo acute pulmonary MRSA infection model in neutropenic rats, where it demonstrated antibacterial activity that was superior to that of inhaled vancomycin.…”

“…To address this, the group of Konicek set out to design derivatives of vancomycin suitable for inhalation. 210 These analogues resemble telavancin but contain a carbonyl linker at the vancosamine position and no resorcinol modification. Representative amide 40 ( Figure 10 ) was selected for extensive investigation due to (1) its potent in vitro activity against target bacteria MRSA (MIC = 0.015 μg/mL), S. pneumoniae (MIC = 0.008 μg/mL), C. difficile (MIC = 0.015–0.06 μg/mL), VanA-type VRE (MIC = 0.03–2 μg/mL), and VanB-type VRE (MIC = 0.03 μg/mL) ( Table 1 ) and (2) its prolonged exposure time after inhalation in rats, with a half-life of 108 h, minimal conversion to the hydrolysis product, and minimal systemic toxicity.…”

“…141,143,156 In an effort to confer selectivity to glycopeptide antibiotics and to minimize their toxicity, targeted approaches have been investigated wherein conjugation to large systems (nanoparticles or living organisms such as algae) or specific tissuetargeting moieties allows for preferential delivery to the target site. 200,202,205,210 In addition, exploitation of specific Gramnegative bacterial uptake receptors has also been investigated through the conjugation of glycopeptides antibiotics to siderophores. 218,219,225 As different bacteria employ a multitude of different siderophore transporters, this approach has the potential to generate species-or even strain-selective antibiotics.…”

Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery

“…Among therapeutics that have been shown to accumulate in macrophages are bedaquiline, oritavancin, and telavancin [55][56][57]. Novel vancomycin derivatives have also demonstrated the ability to target intracellular infections [58].…”