Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant

Dugourd, Dominique; Yang, Haiyan; Elliott, Melissa; Siu, Raymond; Clement, Jacob J.; Straus, Suzana K.; Hancock, Robert E. W.; Rubinchik, Evelina

doi:10.1128/aac.00322-11

Cited by 29 publications

(17 citation statements)

References 28 publications

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“…Drug binding either to surfactantassociated proteins or to phospholipids was blamed for the reduced antimicrobial activity. In contrast, other antibiotics, such as telavancin, vancomycin, ceftazidime, and amoxicillin, remain unaffected by surfactant in vitro (3)(4)(5). This fact bears importance for the choice of antibiotics to successfully treat lower RTI.…”

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confidence: 97%

“…The possibility cannot be excluded that the inhibition of antibiotic activity by PS might be dependent on the concentration of PS in vivo. Nevertheless, this study is the first that systematically evaluates whether there is any impact of PS on the activity of antibiotics of different classes by using PS concentrations corresponding to those previously used in experiments with bovine lung extractbased surfactant (5). Beyond that, regardless of what concentrations of PS are used in vitro for revealing its principal impact on the activity of select antibiotics, the clinical relevance of such findings for in vivo conditions must be examined thoroughly in separate studies.…”

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confidence: 99%

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Effect of Pulmonary Surfactant on Antimicrobial Activity In Vitro

Schwameis

Erdogan-Yildirim

Manafi

et al. 2013

Antimicrob Agents Chemother

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Time-kill curve experiments were performed with linezolid, doripenem, tigecycline, moxifloxacin, and daptomycin against Staphylococcus aureus and with colistin, moxifloxacin, and doripenem against Pseudomonas aeruginosa to evaluate the effect of porcine pulmonary surfactant on antimicrobial activity. Pulmonary surfactant significantly impaired the activities of moxifloxacin and colistin. When antibiotics are being developed for respiratory tract infections, the method described here might be used to preliminarily quantify the effect of pulmonary surfactant on antimicrobial activity. G enerally, the susceptibilities of bacterial strains to antimicrobial agents are determined by comparing the MICs in standard nutrient solutions, i.e., Mueller-Hinton broth (MHB), with established breakpoints. This information is used to predict the clinical efficacy of an antimicrobial agent against a bacterial strain. However, one must consider that, apart from antimicrobial susceptibility, the characteristics of different infection sites may also affect the pharmacodynamic activity of antibiotics. This, for example, has already been described for the activity of fosfomycin in cerebrospinal fluid (1).Until today, only a few studies investigated the effect of pulmonary surfactant (PS) on the activity of antibiotics (2, 3). In these studies, the efficacy of some antibiotics was negatively affected by PS. Indeed, it was observed that daptomycin and tobramycin, both highly effective in vitro against pathogens responsible for respiratory tract infections (RTI), preclinically or clinically failed in the presence of PS (2, 3). Drug binding either to surfactantassociated proteins or to phospholipids was blamed for the reduced antimicrobial activity. In contrast, other antibiotics, such as telavancin, vancomycin, ceftazidime, and amoxicillin, remain unaffected by surfactant in vitro (3-5). This fact bears importance for the choice of antibiotics to successfully treat lower RTI.Although there may be appropriate methods to obtain human alveolar surfactant, it is difficult to obtain and probably impossible to obtain in large amounts for in vitro experiments due to ethical concerns. Therefore, we had to use a surrogate for our experiments. While recent in vitro studies used bovine surfactant to evaluate its effect on antimicrobial activity (2, 3), this is the first study using porcine surfactant. Porcine surfactant was used because clinical studies showed superiority of porcine surfactant over other types of mammalian surfactant for treatment of respiratory distress syndrome (6, 7).In general, MHB (Merck, Darmstadt, Germany) was cation adjusted to a level of 25 mg/liter Ca 2ϩ and 12.5 mg/liter Mg 2ϩ and served as the reference medium. For experiments with daptomycin, MHB was supplemented with Ca 2ϩ to a final level of 50 mg/ liter as recommended by the CLSI (8).For settings testing the influence of PS, cation-adjusted MHB was enriched with porcine surfactant (Curosurf; Chiesi Pharmaceuticals GmbH, Vienna) to a final concentration of 1 mg/ml (M...

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confidence: 97%

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confidence: 99%

Effect of Pulmonary Surfactant on Antimicrobial Activity In Vitro

Schwameis

Erdogan-Yildirim

Manafi

et al. 2013

Antimicrob Agents Chemother

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“…At present, daptomycin is the only clinically used CDA, and its mode of action is the topic of ongoing investigation 6, 7, 8, 9. By comparison, the structurally similar CDAs laspartomycin C, friulimycin B, tsushimycin, and amphomycin have more clearly understood antibacterial mechanisms 10, 11, 12, 13, 14. It was recently reported that laspartomycin C forms a high‐affinity complex ( K d =7.3±3.8 n m ) with the bacterial cell wall precursor undecaprenyl phosphate (C 55 ‐P) and in doing so inhibits peptidoglycan biosynthesis, ultimately leading to cell death 14.…”

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A High‐Resolution Crystal Structure that Reveals Molecular Details of Target Recognition by the Calcium‐Dependent Lipopeptide Antibiotic Laspartomycin C

et al. 2017

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The calcium‐dependent antibiotics (CDAs) are an important emerging class of antibiotics. The crystal structure of the CDA laspartomycin C in complex with calcium and the ligand geranyl‐phosphate at a resolution of 1.28 Å is reported. This is the first crystal structure of a CDA bound to its bacterial target. The structure is also the first to be reported for an antibiotic that binds the essential bacterial phospholipid undecaprenyl phosphate (C55‐P). These structural insights are of great value in the design of antibiotics capable of exploiting this unique bacterial target.

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“…MX-2401 is a novel semisynthetic lipopeptide based on the amphomycin core (17) with potent in vitro activity against resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, vancomycin-resistant Enterococcus spp., and penicillin-resistant Streptococcus pneumoniae (11,15). MX-2401 has been shown to be effective in animal models of peritonitis and thigh and lung infection (18).…”

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confidence: 99%