Abstract
Overexpression of ramA has been implicated in resistance to multiple drugs in several enterobacterial pathogens. In the present study, Salmonella Typhimurium strain LTL with constitutive expression of ramA was compared to its ramA-deletion mutant by employing both DNA microarrays and phenotype microarrays (PM). The mutant strain with the disruption of ramA showed differential expression of at least 33 genes involved in 11 functional groups. The study confirmed at the transcriptional level that the constitutive expression of ramA was directly associated with increased expression of multidrug efflux pump AcrAB-TolC and decreased expression of porin protein OmpF, thereby conferring multiple drug resistance phenotype. Compared to the parent strain constitutively expressing ramA, the ramA mutant had increased susceptibility to over 70 antimicrobials and toxic compounds. The PM analysis also uncovered that the ramA mutant was better in utilization of 10 carbon sources and 5 phosphorus sources. This study suggested that the constitutive expression of ramA locus regulate not only multidrug efflux pump and accessory genes but also genes involved in carbon metabolic pathways.
Highlights
Active efflux by AcrAB-TolC plays an important role in conferring multidrug resistance (MDR) in salmonellae [1]
Typhimurium LTL genome displayed $2-fold differential expression with a P value,0.01 when ramA was inactivated by inserting kanamycin resistance gene, aph (Table 1)
The role of RamA as a transcriptional regulator has been associated with MDR in Salmonella and other Enterobacteriaceae [9,11,25,50]
Summary
Active efflux by AcrAB-TolC plays an important role in conferring multidrug resistance (MDR) in salmonellae [1]. Mutants lacking acrA, acrB, or tolC were attenuated via differential expression of major operons and proteins involved in pathogenesis globally [3]. The ramA locus, when cloned in E. coli, elicited resistance to multiple antibiotics, decreased expression of the OmpF porin, and increased expression of the efflux AcrAB [16]. Typhimurium failed to confer increased susceptibilities to antibiotics [11]. Van der Straaten et al [21] showed that soxR/S was not the only regulon involved in protective response of Salmonella to macrophage-derived oxidative stress and that ramA played an important role in resistance to superoxide and nitrogen intermediates produced by phagocytes as well
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