Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins

Abstract

Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria.

Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to β-Lactam Antibiotics by Acidic pH

“…This issue is further complicated with the example in hand, because Bocillin FL, a ␤-lactam molecule, binds to all PBPs. It is known that inhibition of a mere fraction of PBP of any one kind is sufficient to kill the organism (36). Hence, at pH 7.0 a smaller fraction of PBPs are likely inhibited, but the function of PBP 2a is the reason that the organism survives in the face of the antibiotic challenge.…”

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“…Other drugs that could be tested are Lactivicinas (LTV) that inhibits PBPs but their structure does not contain the -lactam ring and thus is resistant to the action oflactamases, are active against clinical isolates of Streptococcus pneumoniae resistant to penicillin (Macheboeuf, 2007).…”

Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates

“…However, lactivicin has poor penetration into Gram-negative bacteria and is susceptible to at least some ␤-lactamase enzymes (2)(3)(4). A deeper understanding of the interactions between lactivicin and its derivatives and their various enzyme targets has led to the rational design of synthetic derivatives with higher potency against bacteria and reduced susceptibility to ␤-lactamases (1,5,6), including LTV13, which has the "ATMO"-type side chain (6) (Fig. 1C).…”

“…Unlike the ␤-lactams, which remain the most important antimicrobial class, lactivicin contains cycloserine and ␥-lactam motifs, but like the ␤-lactams, lactivicin reacts covalently with PBPs to form a stable acyl-enzyme complex (1) (Fig. 1A and B).…”