Bacterial DNA polymerase III (Pol III) (Pol III)

Bacterial DNA polymerase III (Pol III) is the primary enzyme complex responsible for the replication of the bacterial chromosome [7, 13]. It is a multi-subunit holoenzyme that exhibits high processivity and fidelity, essential for rapid and accurate genome duplication during cell division [11, 17]. The enzyme consists of a catalytic core (alpha, epsilon, and theta subunits), a sliding clamp (beta subunit) for processivity, and a clamp loader complex [7, 8]. In many bacteria, Pol III exists in two main forms: PolC, predominant in low-GC Gram-positive bacteria, and DnaE, found in Gram-negative bacteria and Mycobacteria [4, 15]. Because Pol III is structurally distinct from eukaryotic DNA polymerases, belonging to the C-family rather than the B-family, it serves as an attractive target for the development of narrow-spectrum and broad-spectrum antibiotics [14, 19]. Inhibitors such as ibezapolstat target the PolC subunit by mimicking natural nucleotides and sequestering the enzyme into inactive complexes, effectively halting bacterial growth [18, 21]. This target is particularly relevant for treating infections like Clostridioides difficile and multidrug-resistant tuberculosis [22, 26]. Recent clinical developments have focused on narrow-spectrum inhibitors that minimize damage to the host microbiome [18, 22].

Other names

DNA polymerase III holoenzymePol III HEReplicative DNA polymeraseC-family DNA polymeraseDNA-directed DNA polymerase IIIPolCDnaE

Inhibition of DNA synthesis by competing with natural nucleotides (e.g., dGTP) or sequestering the enzyme into inactive ternary complexes with DNA; some inhibitors also disrupt the interaction between the polymerase and the sliding clamp (beta-clamp/DnaN).