作者: Bragonzi, Alessandra ; Chevalier, Eric ; Dale, Glenn E. ; Obrecht, Daniel ; De Fino, Ida ; Schmitt, Michel ; Bernardini, Francesca ; Cigana, Cristina ; Facchini, Marcella ; Rossi, Alice ; Riva, Camilla ; Alcalá-Franco, Beatriz ; Brodmann, Maj ; Wach, Achim ; Ranucci, Serena ; Misson, Pauline

ABSTRACT The clinical development of antibiotics with a new mode of action combined with efficient pulmonary drug delivery is a priority against untreatable Pseudomonas aeruginosa lung infections. POL7001 is a macrocycle antibiotic belonging to the novel class of protein epitope mimetic (PEM) molecules with selective and potent activity against P. aeruginosa . We investigated ventilator-associated pneumonia (VAP) and cystic fibrosis (CF) as indications of the clinical potential of POL7001 to treat P. aeruginosa pulmonary infections. MICs of POL7001 and comparators were measured for reference and clinical P. aeruginosa strains. The therapeutic efficacy of POL7001 given by pulmonary administration was evaluated in murine models of P. aeruginosa acute and chronic pneumonia. POL7001 showed potent in vitro activity against a large panel of P. aeruginosa isolates from CF patients, including multidrug-resistant (MDR) isolates with adaptive phenotypes such as mucoid or hypermutable phenotypes. The efficacy of POL7001 was demonstrated in both wild-type and CF mice. In addition to a reduced bacterial burden in the lung, POL7001-treated mice showed progressive body weight recovery and reduced levels of inflammatory markers, indicating an improvement in general condition. Pharmacokinetic studies indicated that POL7001 reached significant concentrations in the lung after pulmonary administration, with low systemic exposure. These results support the further evaluation of POL7001 as a novel therapeutic agent for the treatment of P. aeruginosa pulmonary infections.

2010-04-01·Nature Reviews Drug Discovery1区 · 医学

New strategy to target Pseudomonas

1区 · 医学

Article

作者: Flemming, Alexandra

A review.The research of Srinivas et al. (2010) entitled 'Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa' is reviewed with commentary and referencesThese authors report the discovery of a new family of antibiotics with high specificity for Pseudomonas aeruginosa, infections of which pose a serious problem in hospitals and in patients with cystic fibrosis.The development of the new antibiotics was based on previously synthesized β-hairpin-shaped peptidomimetics of the host-defense peptide protegrin I (PG-I), which lyses cell membranes.Starting from a compound that had broad-spectrum antimicrobial activity like that of PG-I, but reduced capacity to lyse human blood cells, lead compounds were optimized by iterative cycles of peptidomimetic library synthesis and screening for microbial activity.

2010-02-19·Science1区 · 综合性期刊

Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

1区 · 综合性期刊

Article

作者: Srinivas, Nityakalyani ; Käch, Andres ; Robinson, John A. ; Henze, Heiko ; Dias, Ricardo L. A. ; Zumbrunn, Jürg ; Jetter, Peter ; DeMarco, Steven J. ; Zerbe, Katja ; Obrecht, Daniel ; Steinmann, Jessica ; Bernardini, Francesca ; Misson, Pauline E. ; Hunziker, Peter ; Werneburg, Martina ; Schauer, Stefan ; Gombert, Frank O. ; Ziegler, Urs ; Ueberbacher, Bernhard J. ; Lederer, Alexander ; Riedel, Kathrin ; Eberl, Leo ; Van der Meijden, Benjamin

Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.

100 项与 POL-7001 相关的药物交易

登录后查看更多信息