Repromicin derivatives with potent antibacterial activity against Pasteurella multocida
J W McFarland1, S J Hecker, B H Jaynes
1Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA. mcfarland@pfizer.com
Journal of Medicinal Chemistry
|March 14, 1997
Summary
New macrolide antibacterial agents derived from repromicin show high potency against Pasteurella multocida. A specific derivative effectively controlled swine pasteurellosis and cattle respiratory disease in vivo.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Veterinary Medicine
Background:
- Macrolide antibiotics are crucial for treating bacterial infections.
- Repromicin, a known macrolide, was chemically modified to explore new antibacterial agents.
- Lipophilicity was identified as a factor influencing in vivo activity of macrolides.
Purpose of the Study:
- To synthesize and evaluate novel macrolide antibacterial agents derived from repromicin.
- To identify compounds with potent activity against Gram-negative pathogens, specifically Pasteurella multocida.
- To assess the in vivo efficacy of promising derivatives in animal models.
Main Methods:
- Reductive amination of repromicin with various polyfunctional amines.
- In vitro testing of synthesized compounds against Pasteurella multocida.
- In vivo efficacy studies in mouse, swine, and cattle infection models.
- Evaluation of structure-activity relationships, focusing on lipophilicity.
Main Results:
- Several new macrolide derivatives demonstrated potent in vitro activity against Pasteurella multocida.
- A key derivative, 20-[N-[3-(dimethylamino)-propyl]-N-L-alanylamino]-20-deoxorepromicin (35), was identified.
- Compound 35 showed significant control of induced pasteurellosis in swine and respiratory disease in cattle at a 5 mg/kg dose.
Conclusions:
- Reductive amination of repromicin yields potent antibacterial agents against Pasteurella multocida.
- Optimizing lipophilicity is critical for enhancing in vivo efficacy of macrolide antibacterials.
- Repromicin derivative 35 represents a promising therapeutic candidate for treating Gram-negative bacterial infections in livestock.
Related Concept Videos
01:28Antimicrobial Effectiveness
The effectiveness of antimicrobial agents depends on various factors influencing their ability to eliminate microbial populations. Larger microbial populations require more time for complete eradication, emphasizing the importance of population size analysis when evaluating antimicrobial efficacy.Microbial resistance to antimicrobial agents varies significantly. Highly resilient microorganisms include endospores, gram-negative bacteria, and non-enveloped viruses, while prions are exceptionally...
01:25Mechanism of Antibiotic Resistance in MRSA
Antibiotic resistance in bacteria arises when microorganisms evolve the ability to withstand drugs designed to kill them or inhibit their growth, rendering once-effective treatments useless. This phenomenon, driven by genetic change and selection under antibiotic exposure, poses a profound threat to modern medicine. Mechanisms include drug-inactivating enzymes (e.g., β-lactamases), efflux pumps that eject antibiotics, mutations altering antibiotic targets, decreased drug uptake, and acquisition...
01:23Inhibitors of Gram-positive Cell Wall Synthesis
Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
01:25Inhibitors of Bacterial Protein Synthesis
Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
01:28Inhibitors of Bacterial DNA Synthesis
Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
01:25Clinical Significance of Antibiotic Resistance
Methicillin-resistant Staphylococcus aureus (MRSA) presents a critical public health threat, arising from its capacity to resist β-lactam antibiotics due to acquisition of the mecA gene within the staphylococcal cassette chromosome mec (SCCmec). This gene encodes penicillin-binding protein 2a (PBP2a), which impairs binding efficacy of methicillin and other β-lactams. MRSA has evolved into distinct clonal lineages impacting humans and animals alike, reinforcing its significance within the One...