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Cephalosporin resistance, tolerance, and approaches to improve their activities
Alison H Araten1, Rachel S Brooks2, Sarah D W Choi1
1Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Abstract:
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
Insights
Cephalosporins are vital antibiotics for Gram-negative infections. This review covers their discovery, action, and the growing challenge of bacterial resistance, tolerance, and persistence, exploring new treatment strategies.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Cephalosporins, a class of β-lactam antibiotics, are crucial for treating Gram-negative bacterial infections by disrupting peptidoglycan synthesis.
- Their efficacy is threatened by increasing global cephalosporin resistance, heteroresistance, tolerance, and persistence.
Purpose of the Study:
- To review the discovery, mechanisms of action, and clinical applications of cephalosporins.
- To discuss the causes of cephalosporin treatment failure, including resistance and subpopulation phenomena.
- To explore emerging strategies like cephalosporin conjugates and combination treatments.
Main Methods:
- Literature review of cephalosporin discovery and mechanisms.
- Analysis of factors contributing to cephalosporin resistance and treatment failure.
- Examination of novel therapeutic approaches.
Main Results:
- Cephalosporins effectively target Gram-negative bacteria by inhibiting cell wall synthesis.
- Bacterial resistance, heteroresistance, tolerance, and persistence are significant challenges to cephalosporin therapy.
- Cephalosporin conjugates and combination therapies show promise in overcoming resistance.
Conclusions:
- Understanding the mechanisms of cephalosporin action and resistance is critical for effective treatment.
- Addressing resistance, heteroresistance, tolerance, and persistence is essential to maintain cephalosporin efficacy.
- Novel therapeutic strategies are needed to combat multi-drug resistant pathogens and reinvigorate the cephalosporin class.
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