The aim of the work described in this thesis is to elucidate the mechanisms of toxic compound resistance employed by L. lactis and to examine the physiological responses when one of the key mechanisms, transporter-based efflux, is genetically inactivated. Chapter 1 provides an introduction to transporter and non-transporter based resistance mechanisms in Gram-positive bacteria with special reference to lactic acid bacteria. In addition, the
mechanism of surface adherence and biofilm development is discussed.
Chapter 2 describes how L. lactis cells devoid of the main MDR and cholate transporter LmrCD can regain resistance when exposed to increasing levels of cholate. The resultant cholate-adapted strain (∆lmrCDr) showed a number of alterations when compared to its parental strain, the drug-sensitive L. lactis NZ9000 ∆lmrCD. The ∆lmrCDr cells exhibit (i) improved resistance toward several bile acids but not to drugs, (ii) an altered susceptibility to antimicrobial peptides, and (iii) morphological changes including a tendency to autoaggregate and flocculate in liquid media. Transcriptome and transport analyses suggest that the acquired resistance is transport unrelated but instead arises from various stress responses, changes to the cell envelope and alterations in metabolism. In contrast, wild-type cells induce the expression of lmrCD upon exposure to cholate, whereupon the cholate is actively extruded from the cells. Together, these data suggest a central role for an efflux-based mechanism in bile acid resistance and implicate LmrCD as the main system responsible in planktonic L. lactis.
Chapter 3 examines how bile acids influence surface adhesion and biofilm development by the cholate resistant ∆lmrCDr strain. Importantly, the results show that bile acids stimulate biofilm formation and render these structures highly resistant to such compounds. This increased biofilm formation appears to be related to the production of extracellular polysaccharides. In addition, the physicochemical aspects of the altered cell surface were studied.
Chapter 4 examines the ability of L. lactis cells lacking the LmrCD transporter to regain resistance to the cationic dye rhodamine 6G and to develop multidrug resistance. Obtained resistant strains show a multidrug resistance phenotype, and express several uncharacterized efflux transporters.
However, the resistance phenotype is likely broader than transporter-based alone, as also metabolic and physiological changes are observed. The data indicate that L. lactis is equipped with cryptic resistance mechanisms that can be activated upon long-term exposure to toxic compounds and provide multiple lines of defense. Finally, Chapter 5 summarizes the results presented in the thesis and discusses the broader implications of the work.
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