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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
For these penicillin analogues, susceptibility to β-lactamase is an issue. However, when used in combination with clavulanic acid, the scope of antibiotics such as amoxicillin is greatly improved. Administered to the patient as Augmentin, the dose level of amoxicillin can be greatly decreased when used in combination with clavulanic acid because clavulanic acid is an irreversible inhibitor of most β-lactamases. It was first isolated from Streptomyces clavuligerus by Beechams in 1976.
Amoxicillin–Clavulanic Acid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Amoxicillin–clavulanic acid is a combination product consisting of the semisynthetic antibiotic amoxicillin with the beta-lactamase-inhibitor clavulanic acid as a potassium salt. Clavulanic acid is a naturally occurring beta-lactamase inhibitor isolated from Streptomyces clavuligerus (Brown et al., 1976; Reading and Cole, 1977; see Chapter 13, Beta-Lactamase inhibitors). It contains a beta-lactam ring, and the sulfur of the penicillin thiazolidine ring is replaced with oxygen to form an oxazolidine ring (see Figure 14.1). Clavulanic acid has weak intrinsic beta-lactam activity, but its clinical utility relates to its potent inhibition of many beta-lactamases (Reading et al., 1983) and its ability to protect substrate drugs from hydrolysis (Bush, 1988). The molecular formula of clavulanic acid is C8H8KNO5. Chemically, clavulanate potassium is potassium –(2R,5R)-3-(2-hydroxyethylidine)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and has a molecular weight of 237.25.
β-Lactam/β-Lactamase Inhibitors
Published in Thomas T. Yoshikawa, Shobita Rajagopalan, Antibiotic Therapy for Geriatric Patients, 2005
To combat the growing problem of β-LACTAMASE-mediated resistance, two strategies became evident: either design (-lactams resistant to the hydrolytic action of β-LACTAMASES or find inhibitors of these enzymes. Clavulanate 1, sulbactam 2, and tazobactam 3 are the major β-LACTAMASE inhibitors used in combination with P-lactams for the treatment of community and nosocomially acquired infections (Fig. 2). Clavulanate is produced naturally by the fungus Streptomyces clavuligerus. Sulbactam and tazobactam are synthetic penicillins that are the product of the pharmaceutical industry medicinal chemists. The contribution of this class of antibiotics (also termed “suicide” inhibitors) to our therapeutic armamentarium cannot be overstated. In this chapter, we will first address how β-LACTAMASE inhibitors inactivate class A β-LACTAMASES, describe briefly the problem of inhibitor-resistant β-LACTAMASES, review important pharmacological and clinical issues related to their use, and discuss the most appropriate application in a clinical setting the geriatrician is likely to
Selected strategies to fight pathogenic bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Aiva Plotniece, Arkadij Sobolev, Claudiu T. Supuran, Fabrizio Carta, Fredrik Björkling, Henrik Franzyk, Jari Yli-Kauhaluoma, Koen Augustyns, Paul Cos, Linda De Vooght, Matthias Govaerts, Juliana Aizawa, Päivi Tammela, Raivis Žalubovskis
Vaborbactam (Scheme 2) is an example of a synthetic β-lactamase inhibitor that is used in combination with meropenem, an intravenous β-lactam antibiotic susceptible to degradation by metallo-β-lactamases. The FDA-approved meropenem-vaborbactam combination complements other β-lactamase inhibitors, such as clavulanic acid, a secondary metabolite of Streptomyces clavuligerus. The Klebsiella pneumoniae β-lactamase is only weakly inhibited by clavulanic acid, which therefore has no clinically relevant use against infections caused by K. pneumoniae7. Vaporbactam is a potent inhibitor of K. pneumonia carbapenemase with no observable concomitant off-target inhibition of mammalian serine proteases. However, vaborbactam does not inhibit class B metallo-β-lactamases, thus, further search for compounds with even wider β-lactamase spectrum is warranted. The key steps in the vaborbactam synthesis involve iridium (I)-catalyzed regioselective hydroboration of an allyl precursor, stereoselective chloromethylation of pinanediol boronate, and a stereospecific substitution of the chloro substituent with lithium hexamethylsilazide8.
Determination and identification of antibiotic-resistant oral streptococci isolated from active dental infections in adults
Published in Acta Odontologica Scandinavica, 2018
Juan Pablo Loyola-Rodriguez, Maria Elena Ponce-Diaz, Alejandra Loyola-Leyva, Jose O. Garcia-Cortes, Carlo E. Medina-Solis, Azael A. Contreras-Ramire, Eduardo Serena-Gomez
Another antibiotic used in oral infections is clavulanic acid (CA), which is a broad-spectrum sz-lactamase inhibitor produced from Streptomyces clavuligerus, with bactericidal activity against both Gram-positive and Gram-negative bacteria. Although CA itself has minimal antibacterial in vitro activity, when combined with beta-lactam antibiotics (amoxicillin) enhances its activity against none-sz-lactamase producing microorganisms. Besides, it has a promising activity against pathogens that cause bone infections [33]. However, some clinicians prefer the combination of A-CA due to the low level of bacterial resistance to this combination, broad-spectrum action, pharmacokinetic profile and tolerance [11]. It has been reported that A-CA had a small frequency of ARB compared with A-CA in active dental infections in primary and permanent dentitions [6,32]. These findings are in agreement with our results and reports from different countries, which suggest that A-CA is an excellent antibiotic alternative for refractory dental infections, especially in acute endodontic abscesses/cellulitis [33–35]. It has been reported that A-AC had a bactericidal activity of 98.8% and the presence of 20% of ARB (these studies were focused on anaerobic bacteria) [20,36]. In this study, A-CA was assessed against oral streptococci for bactericidal activity and ARB, and it showed a bactericidal effect of >99% and a small frequency of ARB (2.8%).
Neuroprotective effect of clavulanic acid on trimethyltin (TMT)-induced cytotoxicity in PC12 cells
Published in Drug and Chemical Toxicology, 2019
Samaneh Silakhori, Hossein Hosseinzadeh, Fatemeh Shaebani Behbahani, Soghra Mehri
Clavulanic acid (CA), a member of the β-lactam family that was first purified from Streptomyces clavuligerus (Saudagar et al.2008). CA has weak antibacterial activity and uses in combination with other β-lactam family antibiotic to increase the spectrum of activity (Lynch and Yang, 2004).