Role of Acinetobacter baumannii UmuD Homologs in Antibiotic Resistance Acquired through DNA Damage-Induced Mutagenesis

Abstract

cThe role of Acinetobacter baumannii ATCC 17978 UmuDC homologs A1S_0636-A1S_0637, A1S_1174-A1S_1173, and A1S_1389 (UmuD Ab ) in antibiotic resistance acquired through UV-induced mutagenesis was evaluated. Neither the growth rate nor the UV-related survival of any of the three mutants was significantly different from that of the wild-type parental strain. However, all mutants, and especially the umuD Ab mutant, were less able to acquire resistance to rifampin and streptomycin through the activities of their error-prone DNA polymerases. Furthermore, in the A. baumannii mutant defective in the umuD Ab gene, the spectrum of mutations included a dramatic reduction in the frequency of transition mutations, the mutagenic signature of the DNA polymerase V encoded by umuDC.

Differential Roles of Antimicrobials in the Acquisition of Drug Resistance through Activation of the SOS Response in Acinetobacter baumannii

“…As shown in Fig. 2, there was a clear correlation between the increased expression of several umuDC genes and the increase in mutagenesis, which might be explained by the direct action of the errorprone DNA polymerase V (encoded by the umuDC genes) in the generation of antibiotic resistance, including to rifampin, as we recently demonstrated (7). Specifically, mutagenesis increased significantly after the treatment of A. baumannii cultures with the MC2h of either ciprofloxacin or tetracycline (P Ͻ 0.01), whereas the induction of mutagenesis was not augmented in response to the MC2h of either meropenem or colistin (Fig.…”

“…baumannii contains multiple umuDC operons and unlinked umuC and umuD genes, all of which encode components of errorprone DNA polymerase V (6). In A. baumannii strain ATCC 17978, the induction of these components after DNA damage leads to the introduction of point mutations in the bacterial genome, including those able to generate antibiotic resistance (7,8). Previous studies showed that the umuD and umuC genes of A. baumannii are induced by ciprofloxacin, which is also a strong inducer of the SOS response (6).…”

“…Previous studies showed that the UmuDAb regulon, encoding several error-prone DNA polymerase V subunits, is an important component of the SOS response and mutagenesis in A. baumannii (6)(7)(8). Point mutations in the bacterial genome caused by these error-prone DNA polymerases can result in the acquisition of drug resistance.…”

“…We recently demonstrated that inactivation of any of the umuD genes present in the genome of A. baumannii ATCC 17978 significantly decreases its ability to generate DNA damage-induced mutants (7). To measure the capacity of the antimicrobials tested in this study to induce mutagenesis in A. baumannii, we used an established rifampin resistance assay for this bacterial species (6).…”

Novobiocin Inhibits the Antimicrobial Resistance Acquired through DNA Damage-Induced Mutagenesis in Acinetobacter baumannii

“…As in other bacteria, A. baumannii achieves resistance against certain antimicrobials through single mutations in the corresponding target genes (i.e., point mutations in the rpoB gene can generate resistance to rifampin [2]). In previous works, we demonstrated that this bacterium contains multiple components of error-prone DNA polymerases, whose induction after DNA damage leads to the introduction of point mutations in the bacterial genome, including those conferring antibiotic resistance (3,4).…”