Development of new drugs for an old target: the penicillin binding proteins

Abstract

The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs). PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics.

Figure 1

β-lactam antibiotics.

Figure 2

Reaction of natural substrates (peptidoglycan stem-peptides), of suicide substrates (β-lactams) and transition state analogs with reactive serine residue in the active site of PBPs.

Figure 3

β-lactamase inhibitors and examples of the new generation of β-lactam antibiotics.

Figure 4

Molecules used for assay design.

Figure 5

Boronic acids.

Figure 6

Views from a crystal structure of R39 in complex with 6 (white) and 7 (yellow). The benzyl group of 7 occupies a region predicted by computational analysis.

Figure 7

Reaction scheme and overlap of monocovalent adduct (white) and tricovalent adduct (gold) of 11 with R39. Oxygen atoms are coloured red, nitrogen blue, boron pink and chlorine green [58].

Figure 8

Carbonyl compounds.

Figure 9

Phosph(on)ates.

Figure 10

Substrate analogs.

Figure 11

Reaction of lactivicin in the active site of S. pneumoniae PBP1b [100].

Figure 12

Non-covalent inhibitors.