Inhibition of the Antibiotic Activity of Cephalosporines by Co-Crystallization with Thymol
Cecilia Fiore, Alessandra Baraghini, Oleksii Shemchuk, Vittorio Sambri, Manuela Morotti, Fabrizia Grepioni, Dario Braga
Abstract
Three structurally similar antibiotics of the cephalosporin (CEPH) class, namely, cephalexin (CPX), cephradine (CFD), and cefaclor (CFC), have been co-crystallized with thymol (THY) via different preparation techniques, yielding the hydrated co-crystals CPX·THY·2.5H2O form I and form II, CFD·THY·2.5H2O, and CFC·THY·4H2O. All co-crystals were structurally characterized by single crystal and/or powder X-ray diffraction. In all co-crystals, except in the case of the elusive metastable form I of CPX·THY·2.5H2O, the CEPH molecules interact with thymol only via water bridges; i.e., there is no direct hydrogen bonding between CEPH molecules and THY. Preliminary antimicrobial experiments via measurements of minimal inhibitory concentration (MIC) provide clear-cut evidence that the association with thymol increases the resistance of both Gram-negative and Gram-positive bacteria to the antibiotic with respect to pure CEPH as well as to physical mixtures of CEPH with thymol.