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Penam sulfones and ?-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition.

ABSTRACT: ?-Lactamases are the major reason ?-lactam resistance is seen in Gram-negative bacteria. To combat this resistance mechanism, ?-lactamase inhibitors are currently being developed. Presently, there are only three that are in clinical use (clavulanate, sulbactam and tazobactam). In order to address this important medical need, we explored a new inhibition strategy that takes advantage of a long-lived inhibitory trans-enamine intermediate. SA2-13 was previously synthesized and shown to have a lower k(react) than tazobactam. We investigated here the importance of the carboxyl linker length and composition by synthesizing three analogs of SA2-13 (PSR-4-157, PSR-4-155, and PSR-3-226). All SA2-13 analogs yielded higher turnover numbers and k(react) compared to SA2-13. We next demonstrated using protein crystallography that increasing the linker length by one carbon allowed for better capture of a trans-enamine intermediate; in contrast, this trans-enamine intermediate did not occur when the C2 linker length was decreased by one carbon. If the linker was altered by both shortening it and changing the carboxyl moiety into a neutral amide moiety, the stable trans-enamine intermediate in wt SHV-1 did not form; this intermediate could only be observed when a deacylation deficient E166A variant was studied. We subsequently studied SA2-13 against a relatively recently discovered inhibitor-resistant (IR) variant of SHV-1, SHV K234R. Despite the alteration in the mechanism of resistance due to the K?R change in this variant, SA2-13 was effective at inhibiting this IR enzyme and formed a trans-enamine inhibitory intermediate similar to the intermediate seen in the wt SHV-1 structure. Taken together, our data reveals that the C2 side chain linker length and composition profoundly affect the formation of the trans-enamine intermediate of penam sulfones. We also show that the design of SA2-13 derivatives offers promise against IR SHV ?-lactamases that possess the K234R substitution.

SUBMITTER: Rodkey EA

PROVIDER: S-EPMC3894197 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Penam sulfones and β-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition.

Rodkey Elizabeth A EA Winkler Marisa L ML Bethel Christopher R CR Pagadala Sundar Ram Reddy SR Buynak John D JD Bonomo Robert A RA van den Akker Focco F

PloS one 20140116 1

β-Lactamases are the major reason β-lactam resistance is seen in Gram-negative bacteria. To combat this resistance mechanism, β-lactamase inhibitors are currently being developed. Presently, there are only three that are in clinical use (clavulanate, sulbactam and tazobactam). In order to address this important medical need, we explored a new inhibition strategy that takes advantage of a long-lived inhibitory trans-enamine intermediate. SA2-13 was previously synthesized and shown to have a lower ...[more]

PMID: 24454944

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Project description:The design guidelines of polymer structure to effectively promote lithium-ion conduction within the polymer electrolytes (PEs) are crucial for its practical use. In this study, the electrolyte properties of a simple polyether having alkyl side chains with varied lengths (-(CH2)m-H, m = 1, 2, 4, 6, 8, and 12) were compared and established a valid design strategy based on the properties of the alkyl side chain. Various spectro-electrochemical measurements successfully connected the electrolyte properties and the alkyl side chain length. Steric hindrance of the alkyl side chain effectively suppressed the interaction between ether oxygen and lithium-ion (m ≥ 2), decreasing the glass transition temperature and the activation energy of lithium-ion transfer at the electrode-electrolyte interface. The strong hydrophobic interactions aligned and/or aggregated the extended alkyl group (m ≥ 8), creating a rapid lithium-ion transport pathway and enhancing lithium-ion conductivity. A clear trend was observed for the following three crucial factors determining bulk lithium-ion transport properties along with the extension of the alkyl side chain: 1) salt dissociability decreased due to the non-polarity of the alkyl side chain, 2) segmental mobility of polymer chains increased due to the internal plasticizing effect, and 3) lithium-ion transference number increased due to the inhibition of the bulky anion transport by its steric hindrance. The highest lithium-ion conductivity was confirmed for the PEs with an alkyl side chain of moderate length (m = 4) at 70°C, indicating the optimized balance between salt dissociability, polymer segmental mobility, and selective lithium-ion transfer. The length of an alkyl side chain can thus be a critical factor in improving the performance of PEs, including thermal stability and lithium-ion conductivity. Precise tuning of the alkyl side chain-related parameters such as steric hindrance, polarity, internal plasticizing effect, and self-alignment optimizes the polymer segmental mobility and salt dissociability, which is crucial for realizing high lithium-ion conductivity for PEs.

Dataset Information

Penam sulfones and ?-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition.

Publications

Penam sulfones and β-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition.

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