Overexpression of efflux pumps is one of the major determinants of resistance in bacteria. Streptomyces harbor a large array of efflux pumps that are transcriptionally silenced under laboratory conditions. However, their dissemination results in multidrug resistance in different clinical pathogens. In this study, we have identified an efflux pump from Streptomyces coelicolor, SCO4121, belonging to the MFS family of transporters and characterized its role in antibiotic resistance. SCO4121, provided resistance to multiple dissimilar drugs upon overexpression into both native and heterologous hosts. Further, deletion of SCO4121 resulted in increased sensitivity towards ciprofloxacin and chloramphenicol, suggesting the pump to be a major transporter of these substrates. Apart from providing multidrug resistance, SCO4121 imparted increased tolerance against the strong oxidant HOCl. In the wild type Streptomyces coelicolor cells, these drugs were found to transcriptionally regulate the pump in a concentration-dependent manner. Additionally, we identified SCO4122, a MarR regulator that positively regulates SCO4121 in response to the various drugs and oxidant HOCl. Thus, through these studies we present the multiple roles of SCO4121 in S. coelicolor and highlight the intricate mechanisms via which it is regulated in response to antibiotics and oxidative stress. IMPORTANCE One of the key mechanisms of drug resistance in bacteria is overexpression of efflux pumps. Streptomyces species are a reservoir of a large number of efflux pumps, potentially to provide resistance to both endogenous and non-endogenous antibiotics. While many of these pumps are not expressed under standard laboratory conditions, they result in resistance to multiple drugs when spread to other bacterial pathogens through horizontal gene transfer. In this study, we have identified a widely conserved, efflux pump, SCO4121 from Streptomyces coelicolor with roles in both multidrug resistance and oxidative stress tolerance. We also report the presence of an adjacently placed MarR regulator, SCO4122 which positively regulates SCO4121 in presence of diverse substrates in a redox-responsive manner. This study highlights that studying soil bacteria such as Streptomyces can reveal novel mechanisms of antibiotic resistance that may potentially emerge in clinically important bacteria.

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