Succinylation of GyrB Is a Mechanism Conferring Fluoroquinolone Resistance

Being a persistent and deadly infection, tuberculosis (TB) caused by Mycobacterium tuberculosis remains a global health challenge. Despite having a well-established 4-drug combination therapy for drug-sensitive TB, the emergence of drug-resistant TB has rendered the treatment less effective. Although fluoroquinolones (FQs) are among the prominent drugs in the second-line treatment for multidrug-resistant tuberculosis (MDR-TB), FQ resistance has readily emerged in cases of extensively drug-resistant tuberculosis (XDR-TB). Other than the mutations in DNA gyrase, a universally conserved bacterial enzyme targeted by FQs, several mechanisms contribute to the emergence of FQ resistance. Recently, post-translational modification of DNA gyrase is implicated as one of the mechanisms for FQ resistance. Here, we describe succinylation of GyrB by a promiscuous acetyltransferase, Eis of M. tuberculosis, as a new mechanism contributing to FQ resistance in mycobacteria. Lysine succinylation of GyrB results in a reduced interaction of FQs with the enzyme, thereby decreasing the DNA cleavage by DNA gyrase in the presence of FQs. Accordingly, Eis overexpressing mycobacterial strains exhibit increased minimum inhibitory concentration (MIC) to FQs. Thus, succinylation of DNA gyrase is yet another resistance mechanism against the FQs.