The combination of clavulanic acid and amoxycillin (Augmentin^R) in the treatment of patients infected with penicillinase producing gonococci

Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

“…The effectiveness of the most important class of antibacterial agents, the β-lactam antibiotics, has been compromised by a main resistance mechanism, the production of β-lactamase enzymes . Co-dosing of β-lactams with a β-lactamase inhibitor (BLI) has been used as a successful strategy to combat this type of resistance as far back as 1981, when the combination of clavulanic acid and amoxycillin was launched . Other established BLIs, such as tazobactam and sulbactam (Figure ), have become less clinically useful because of the increasing resistance attributable to bacterial production of extended spectrum β-lactamases .…”

“…2 Co-dosing of β-lactams with a β-lactamase inhibitor (BLI) has been used as a successful strategy to combat this type of resistance as far back as 1981, when the combination of clavulanic acid and amoxycillin was launched. 3 Other established BLIs, such as tazobactam and sulbactam (Figure 1), have become less clinically useful because of the increasing resistance attributable to bacterial production of extended spectrum β-lactamases. 4 In 2015, the novel diazabicyclooctane (DBO) BLI avibactam entered the clinic 5 in fixed combination with ceftazidime and several "fast followers", including relebactam (approved June 2020), plus nacubactam, zidebactam, and durlobactam, which are in clinical development (Figure 1).…”

Designing Inhibitors of β-Lactamase Enzymes to Overcome Carbapenem Resistance in Gram-Negative Bacteria

“…The SBLs were the earliest to be recognized as a clinical problem, 5 and in the 1970s, screening of natural products led to the discovery of clavulanic acid (2), which is itself a β-lactam that has little antibiotic activity but inhibits Class A SBLs that were prevalent in that decade. 8 Clavulanic acid (marketed as Augmentin in combination with the βlactam amoxycillin) was launched in 1981 9 and was followed by sulbactam and tazobactam, 10 which have a similar limited spectrum of activity. More recently, diazabicyclooctanone (DBO) inhibitors, based on a non-β-lactam scaffold, were designed.…”

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

“…β-Lactamases belong to two structurally and mechanistically unrelated families of enzymes, 4 the serine-β-lactamases (SBLs; classes A, C, and D), which use an active serine to cleave the β-lactam in a covalent mechanism, and the metallo-β-lactamases (MBLs; class B), which use metal ion catalysis to directly hydrolyze the β-lactam without the formation of a covalent intermediate. To counter the threat of emerging resistance, the Streptomyces clavuligerus natural product clavulanic acid ( 2 ), an SBL inhibitor (Scheme 1), was introduced in 1981 as part of a combination together with the β-lactam antibiotic amoxicillin (as Augmentin), 5 followed by tazobactam in 1992, combined with piperacillin. 6 More recently, there has been renewed interest in the field of β-lactamase inhibitor discovery to counter the threat from newer β-lactamases, which are not inhibited by clavulanic acid or tazobactam, such as the extended spectrum β-lactamases (ESBLs) and carbapenemases.…”

“…A major resistance mechanism to β-lactams antibiotics is represented by the production of one or more β-lactamase enzymes, which efficiently hydrolyze the amide bond of the β-lactam ring. β-Lactamases belong to two structurally and mechanistically unrelated families of enzymes, 4 Streptomyces clavuligerus natural product clavulanic acid (2), an SBL inhibitor (Scheme 1), was introduced in 1981 as part of a combination together with the β-lactam antibiotic amoxicillin (as Augmentin), 5 followed by tazobactam in 1992, combined with piperacillin. 6 More recently, there has been renewed interest in the field of β-lactamase inhibitor discovery to counter the threat from newer β-lactamases, which are not inhibited by clavulanic acid or tazobactam, such as the extended spectrum β-lactamases (ESBLs) and carbapenemases.…”