Beta‐lactamases and bacterial resistance to antibiotics

We analyzed several features of five currently available ␦-proteobacterial genomes, including two aerobic bacteria exhibiting predatory behavior and three anaerobic sulfate-reducing bacteria. The ␦ genomes are distinguished from other bacteria by several properties: (i) The ␦ genomes contain two ''giant'' S1 ribosomal protein genes in contrast to all other bacterial types, which encode a single or no S1; (ii) in most ␦-proteobacterial genomes the major ribosomal protein (RP) gene cluster is near the replication terminus whereas most bacterial genomes place the major RP cluster near the origin of replication; (iii) the ␦ genomes possess the rare combination of discriminating asparaginyl and glutaminyl tRNA synthetase (AARS) together with the amidotransferase complex (Gat CAB) genes that modify Asp-tRNA Asn into Asn-tRNA Asn and Glu-tRNA Gln into Gln-tRNA Gln ; (iv) the TonB receptors and ferric siderophore receptors that facilitate uptake and removal of complex metals are common among ␦ genomes; (v) the anaerobic ␦ genomes encode multiple copies of the anaerobic detoxification protein rubrerythrin that can neutralize hydrogen peroxide; and (vi) 54

Section: -Activator Proteins Histidine Kinase (Hk) and Response Regmentioning

confidence: 99%

Distinguishing features of δ-proteobacterial genomes

Karlin¹,

Brocchieri²,

Mrázek

et al. 2006

“…β-lactamases are the most common cause of resistance to β-lactam antibiotics, such as penicillins and cephalosporins; they threaten what remains the most widely used class of antibiotics and have attracted much recent attention (1)(2)(3)(4)(5). Third-and fourth-generation cephalosporins were partly introduced to overcome these enzymes, as were inhibitors like clavulanic acid, but resistance arose rapidly to these agents, which are all themselves β-lactams and thus potential substrates of β-lactamases.…”

mentioning

confidence: 99%

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam¹,

Romagnoli

Dalmasso

et al. 2012

Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.antibiotic resistance | antimicrobial | drug discovery | structure-based | boronic acid

“…By inactivating peptidoglycan transpeptidases, members of the family of penicillin-binding proteins, ␤-lactam antibiotics have been successfully used for many years to inhibit the peptidoglycan synthesis responsible for the biosynthesis of the bacterial cell wall (1,2).…”

mentioning

confidence: 99%

Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis

Santillana

Beceiro

Bou

et al. 2007

108

162

Combating bacterial resistance to ␤-lactams, the most widely used antibiotics, is an emergent and clinically important challenge. OXA-24 is a class D ␤-lactamase isolated from a multiresistant epidemic clinical strain of Acinetobacter baumannii. We have investigated how OXA-24 specifically hydrolyzes the last resort carbapenem antibiotic, and we have determined the crystal structure of OXA-24 at a resolution of 2.5 Å. The structure shows that the carbapenem's substrate specificity is determined by a hydrophobic barrier that is established through the specific arrangement of the Tyr-112 and Met-223 side chains, which define a tunnel-like entrance to the active site. The importance of these residues was further confirmed by mutagenesis studies. Biochemical and microbiological analyses of specific point mutants selected on the basis of structural criteria significantly reduced the catalytic efficiency (kcat/Km) against carbapenems, whereas the specificity for oxacillin was noticeably increased. This is the previously unrecognized crystal structure that has been obtained for a class D carbapenemase enzyme. Accordingly, this information may help to improve the development of effective new drugs to combat ␤-lactam resistance. More specifically, it may help to overcome carbapenem resistance in A. baumannii, probably one of the most worrying infectious threats in hospitals worldwide.␤-lactamases ͉ carbapenem resistance ͉ enzyme mechanism ͉ protein crystallography ͉ Acinetobacter baumannii