title: Factors governing intrinsic chemical reactivity differences between clavulanic and penicillanic acids.
abstract: To help elucidate why penicillin-G is inactivated by certain bacterial beta-lactamase enzymes, whereas clavulanic acid (Clav, which is similar to penicillin-G except at positions 1, 2, and 6) inhibits beta-lactamase, the intrinsic chemical reactivities of these two antibiotics were assessed in this work. Ab initio and continuum dielectric methods were used to map out the gas-phase and solution-phase free-energy profiles for the alkaline hydrolyses of Clav and penicillanic acid (Peni, which is similar to penicillin-G except at position 6) as well as of a fictitious hybrid compound, Peni-db, which is similar to Clav and Peni except at positions 1 and 2, respectively. Furthermore, the ring strain energies of various lactam rings and the five-membered rings of Peni and Clav as well as their respective rate-limiting transition states were computed to assess the contribution of four- and five-membered ring strains to the antibiotic's activity. The predicted product distribution, rate-limiting step, and relative reaction rates for the alkaline hydrolysis of Peni and Clav are in accord with the experimental findings. The rate-limiting step in the alkaline hydrolysis of Peni, Clav, or Peni-db is the approach of the negatively charged hydroxide ion toward the anionic reactant to form a tetrahedral intermediate. The alkaline hydrolysis of Clav generates more stable products than that of Peni mainly because the O1 atom and the hydroxyethylidene group in Clav facilitate the opening of the five-membered ring; furthermore, the O1 atom can abstract a proton easier than the less polar S1 in Peni. Clav undergoes basic hydrolysis faster than Peni mainly because its hydroxyethylidene group leads to an increase in the positive charge on the carbonyl C7 atom, therefore enhancing favorable electrostatic interactions with the incoming hydroxide anion. To a lesser extent, the oxygen at position 1 in Clav also contributes to the rate acceleration because of the greater solvent stabilization of the oxygen-containing transition state as compared to the respective ground state. The inherent strain of the four-membered beta-lactam ring or five-membered ring does not enhance the alkaline hydrolyses of beta-lactam molecules such as Peni or Clav, consistent with the observation that the rate-limiting step does not involve a breakdown of the four-membered beta-lactam ring or five-membered thiazolidine/oxazolidine rings.
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019818:Clavulanic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010397:Penicillanic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012996:Solutions; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D010397:Penicillanic Acid; D001618:beta-Lactamases