Mechanisms of beta-lactam resistance inHaemophilus influenzae
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Penicillin binding proteins
Lactam
Beta-lactam
Upon investigation of penicillin-binding proteins (PBPs) in Haemophilus influenzae strains, five H. influenzae and seven other Haemophilus strains were tested for whole-cell penicillin binding at either 37 or 42 degrees C. Binding of [35S]penicillin G to H. influenzae PBPs 3a and 3b was drastically reduced at 42 degrees C, while PBP 1a showed a temperature-modulated increase in penicillin binding. Further investigation revealed that growth at 42 degrees C causes altered electrophoretic mobility of PBP 3a on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and that cell labeling performed at 42 degrees C showed the differential penicillin binding to target proteins. All Haemophilus spp. tested showed a similar temperature modulation of penicillin binding. Growth measurement and cell viability studies performed at 42 degrees C permitted correlation of PBP 3 temperature sensitivity to H. influenzae resistance to moxalactam at 42 degrees C, and the probable correlation of PBP 1a increased penicillin binding to the more rapid antibacterial activity of penicillin G against H. influenzae at 42 degrees C. Microscopic examination of Haemophilus cells grown at 42 degrees C revealed filamentous cell formation, supporting a role of PBP 3 in the septation process. Results of this study demonstrate that wild-type H. influenzae strains (and possibly all other Haemophilus spp.) possess PBPs 1a and 3, which have distinct and opposite temperature-modulated penicillin-binding activities.
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Haemophilus aegyptius and Haemophilus influenzae biotype III are morphologically and biochemically similar; however, their outer membrane protein (Sarkosyl insoluble) profiles are distinct. Of 18 strains of H. aegyptius examined, 15 had a type 1 protein profile, and 3 had a type 2 profile, whereas the 5 strains of H. influenzae biotype III examined had three other protein profile types. All Haemophilus strains examined had 31- and 76-kilodalton (kDa) proteins and minor proteins with molecular masses between 20 and 100 kDa. H. aegyptius, with a type 1 protein profile, had major outer membrane proteins with apparent molecular masses of 27, 35.5, and 41.5 kDa, and H. aegyptius, with a type 2 protein profile, had 26-, 29-, 39.5-, and 41-kDa proteins. The type strain of H. influenzae biotype III had three major outer membrane proteins with apparent molecular masses of 29, 38.5 and 40 kDa. Four other strains designated as H. influenzae biotype III had major outer membrane proteins between 27 and 41.5 kDa representing two additional protein profiles.
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The key intermediate of monocyclic beta-lactams, N-benzyloxycarbonyl-3 S-amino-2-oxoazetidine(Ⅲ),was synthesized from L-( + )-2,3-diaminopropanoie acid(Ⅰ) by Ph_3P—(PyS)_2—CH_3CN system and N-benzyloxycarbonylation. Ⅰ was prepared from L(+)-aspartic acid by Schmidt rearrangement.Three derivatives(Ⅷa～c) of this monocyclic beta-lactam were prepared and their biological activities evaluated.
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Permeabilized cells of Haemophilus influenzae incorporate wall precursors into murein material in an ampicillin-sensitive reaction. In resistant transformants that contain the low antibiotic affinity penicillin-binding proteins (PBPs) 4 and 5, the sensitivity of this incorporation reaction to ampicillin is proportionally lower, suggesting a catalytic role for these proteins in wall synthesis. We conclude that, analogous to the reaction in Escherichia coli, PBPs 4 and 5 of H. influenzae have transpeptidase activity.
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Permeabilized cells of Haemophilus influenzae incorporate wall precursors into murein material in an ampicillin-sensitive reaction. In resistant transformants that contain the low antibiotic affinity penicillin-binding proteins (PBPs) 4 and 5, the sensitivity of this incorporation reaction to ampicillin is proportionally lower, suggesting a catalytic role for these proteins in wall synthesis. We conclude that, analogous to the reaction in Escherichia coli, PBPs 4 and 5 of H. influenzae have transpeptidase activity.
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Lactam
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A beta-Lactams show high chemical reactivity and ease of molecular rearrangement and a r e therefore potential synthons of value.The present communication reviews the relevant literature and describes observation made in our laboratory and elsewhere.Suitably substituted beta-Lactams can lead to multiheteroatom cyclic compounds of various sizes including derivatives of carbostyril, coumarin, diazepin, oxazepin and thiazepin of potential interest to synthetic and medicinal chemists.
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