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In vitro microbiological characterization of novel macrolide CP-163,505 for animal health specific use
L J Norcia1, S B Seibel, B J Kamicker
1Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Abstract:
A novel 16-membered-ring macrolide agent (CP-163,505, a reductive amination derivative of repromicin) was identified as an antibacterial against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae, important etiological agents of livestock respiratory disease. In vitro MIC50/90 analysis revealed that CP-163,505 was more potent (4x) than tilmicosin against P. multocida, and equivalent to tilmicosin against P. haemolytica and A. pleuropneumoniae. In time kill kinetic studies, CP-163,505 showed bactericidal activity against P. haemolytica, P. multocida and A. pleuropneumoniae and bacteriostatic activity against E. coli at 8 times its MIC. In vitro, CP-163,505 was more potent in alkaline pH (16 approximately 32 x ) and less potent in the presence of excess cations (Mg+2 and Ca+2, 4x). EDTA and PMBN increased CP-163,505 potency against E. coli (4x) but not against the other species. Similar results were obtained with erythromycin A and tilmicosin, which were used as controls. From our data, we hypothesize that Pasteurella and Actinobacillus have an outer membrane significantly different from that of the typical enteric Gram-negative bacterium E. coli.
Insights
A new macrolide antibiotic, CP-163,505, shows potent antibacterial activity against livestock pathogens Pasteurella and Actinobacillus. Its efficacy varies with pH and cations, suggesting unique outer membrane differences compared to E. coli.
Area of Science:
- Veterinary Microbiology
- Medicinal Chemistry
- Antimicrobial Resistance
Background:
- Livestock respiratory diseases caused by Pasteurella haemolytica, Pasteurella multocida, and Actinobacillus pleuropneumoniae result in significant economic losses.
- Novel antimicrobial agents are needed to combat these economically important pathogens.
Purpose of the Study:
- To evaluate the in vitro antibacterial activity of a novel macrolide, CP-163,505, against key livestock respiratory pathogens.
- To compare the efficacy of CP-163,505 with existing antibiotics like tilmicosin.
- To investigate factors influencing CP-163,505 activity, such as pH, cations, and outer membrane permeability.
Main Methods:
- Minimum Inhibitory Concentration (MIC50/90) determination against target bacteria.
- Time-kill kinetic studies to assess bactericidal/bacteriostatic activity.
- In vitro testing of CP-163,505 activity under varying pH, cation concentrations, and in the presence of EDTA and Polymyxin B nonapeptide (PMBN).
Main Results:
- CP-163,505 demonstrated potent activity against P. multocida, P. haemolytica, and A. pleuropneumoniae, outperforming or matching tilmicosin.
- The agent exhibited bactericidal activity against these pathogens and bacteriostatic activity against E. coli.
- CP-163,505 potency was enhanced in alkaline pH and reduced by excess cations, with increased activity against E. coli in the presence of EDTA/PMBN, unlike the other tested species.
Conclusions:
- CP-163,505 is a promising novel macrolide antibiotic for treating livestock respiratory infections.
- The differential activity of CP-163,505 against Gram-negative bacteria suggests unique outer membrane characteristics in Pasteurella and Actinobacillus species compared to E. coli.
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