Avibactam – A New Type of Guardian Angel for β-Lactam Antibiotics
Avibactam is the first non-β-lactam containing broad-spectrum serine β-lactamase inhibitor to be used clinically, and is effective against various classes of serine β-lactamases. The mode of action of avibactam resembles that of the classic β-lactam β-lactamase inhibitors such as clavulanic acid, in which it targets the β-lactamase active site through covalent modification of a catalytically important nucleophilic serine residue. However, contrary to β-lactam inhibitors, this reaction is reversible. The success of avibactam should encourage future efforts to expand the scope of non-β-lactam antibiotics targeting PBPs/β-lactamases.
2016 marks the 75th anniversary of the first clinical administration of penicillin, a β-lactam antibacterial that changed the world for the better. Over the intervening period, penicillins and related compounds, i.e. cephalosporins, monobactams and carbapenems, have emerged as the most important drugs for treating bacterial infections. The common feature of all of these compounds is the presence of the β-lactam ring. While resistance to the β-lactam antibiotics is a pressing issue, the apparent longevity of the dominance of the β-lactams as antibiotics suggests the presence of underlying chemical reasons for their remarkable effectiveness. β-Lactam antibiotics, such as the penicillins, inhibit penicillin binding proteins (PBPs or DD-transpeptidases), which catalyze the cross-linking of peptidoglycan ‘stem peptides’, an essential process in bacterial cell wall biosynthesis. This inhibition occurs by irreversible reaction (acylation) with a catalytically crucial nucleophilic serine residue at the PBP active site.
Resistance towards β-lactam antibiotics occurs via several mechanisms, including via bacterial production of β-lactamases, which react in a similar way to PBPs but form an enzyme-intermediate complex that is readily hydrolyzed, thus rendering β-lactam antibiotics ineffective. β-Lactamases work via two possible mechanisms – one which involves a nucleophilic serine residue (serine β-lactamases, or SBLs) and another involving zinc ion-assisted catalysis (metallo-β-lactamases, or MBLs). One strategy to combat resistance has involved production of modified natural β-lactams, such as penicillins, cephalosporins, monobactams and carbapenems, that evade or inhibit β-lactamase hydrolysis. In particular, SBL inhibitors, such as clavulanic (a naturally occurring clavam), tazobactam and sulbactam, which are themselves β-lactams, have been highly successful from a clinical perspective when used in combination with a β-lactam antibacterial. However, highly resistant bacterial strains to all antibiotics are emerging. There is thus a strong desire to develop entirely new classes of clinically useful antibiotics; however, this has proven difficult. Hence, it is imperative to also look for new ways to protect the most successful classes of existing antibiotics such as the β-lactams.
Scientists have long explored the possibility of non-β-lactam compounds as PBP inhibitors. Lactivicin is a naturally occurring non-β-lactam PBP/SBL inhibitor that employs a similar acylating mechanism as its β-lactam counterparts, but which does not contain a β-lactam ring. Other non-acylating inhibitors, including boronic acids, which act as ‘transition state analogue’ inhibitors, have also been explored. However, none of these have yet seen any clinical success. Hence, the clinical introduction of avibactam, the first clinically useful non-β-lactam containing β-lactamase inhibitor used in combination with a cephalosporin, ceftazidime (marketed as Avycaz), represents a very major advance in the field of combating bacterial infections and resistance. Avibactam acts as a broad-spectrum serine β-lactamase inhibitor with activity against enzymes from all three classes of serine β-lactamases, i.e. penicillinases (class A), cephalosporinases (class C) and, some, oxacillinases (class D). Similar to the classic β-lactam β-lactamase inhibitors, such as clavulanic acid, avibactam reacts with the β-lactamase active site via covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, this reaction is reversible. Although reversible acylation has precedent in ‘academic’ inhibitors of serine proteases, its operation in the clinically useful context of avibactam is pioneering. The avibactam story should inspire future efforts to expand the scope of non-β-lactam antibiotics targeting PBPs/β-lactamases.
For more details, see our comprehensive review article: http://www.future-science.com/doi/full/10.4155/fmc...