Identification of Gip as a novel phage-encoded gyrase inhibitor protein featuring a broad activity profile

Abstract

Bacteriophages represent a powerful source for the identification of novel antimicrobial proteins. In this study, a screening of small cytoplasmic proteins encoded by the CGP3 prophage of Corynebacterium glutamicum, resulted in the identification of the novel gyrase-inhibiting protein Cg1978 (Gip), which shows a direct interaction with the gyrase subunit A (GyrA). In vitro supercoiling assays further suggest a stabilization of the cleavage complex by Gip. Overproduction of Gip in C. glutamicum resulted in a severe growth defect as well as an induction of the SOS response. The cells adapted to gip overexpression by increasing expression levels of gyrAB and by reducing topA expression reflecting the homeostatic control of DNA topology. Interestingly, Gip features a similar activity profile towards gyrases of Escherichia coli, Mycobacterium tuberculosis and C. glutamicum. Therefore, the detailed elucidation of the mechanism of Gip action may provide novel directions for the design of drugs targeting DNA gyrase.