Abstract
Multidrug Transporters (MDTs) are major contributors to the acquisition and maintenance of Antimicrobial Resistance (AMR), a growing public health threat of broad concern. Despite the large number of MDTs, the overwhelming majority of the studies performed thus far in Gram-negative bacteria emphasize the supremacy of the AcrAB-TolC complex. To unveil the potential role of other MDTs we studied the behavior of a null AcrB Escherichia coli strain when challenged with chloramphenicol, a bacteriostatic antibiotic. We found that such a strain developed an extremely high-level of resistance to chloramphenicol, cross resistance to quinolones and erythromycin and displayed high levels of expression of the single component MFS transporter MdfA and multiple TolC-dependent transporters. The results suggest that the high versatility of the whole ensemble of transporters, the bacterial Effluxome, is an essential part of a strategy of survival in everchanging, at times noxious, environments. The concept of a functional Effluxome presents an alternative to the existing paradigms in the field and provides novel targets for the search for inhibitors of transporters as adjuvants of existing antibiotics.
Highlights
Multidrug Transporters (MDTs) are major contributors to the acquisition and maintenance of Antimicrobial Resistance (AMR)
We previously reported the generation in the lab of E. coli strains highly resistant to chloramphenicol through multistep evolution by exposing the cells to sublethal concentration of the drug, increasing it daily two-fold until the bacteria were no longer able to adapt to the amount of chloramphenicol [11]
We used two types of mutants: a triple single-component (EmrE, MdfA and MdtM) knock out strain, and a single tripartite transporter (AcrB) knock out strain. These strains provide an excellent experimental paradigm to analyze the potential role of transporters other than the AcrAB-TolC complex and to try to pinpoint regulatory mechanisms governing the interaction of MDTs in a Gram-Negative organism such as E. coli
Summary
Multidrug Transporters (MDTs) are major contributors to the acquisition and maintenance of Antimicrobial Resistance (AMR). The overwhelming majority of the studies performed far support the central role of AcrAB-TolC complex A systematic assessment of the role of specific genes in resistance to antibiotics and in terms of transporter genes only identified the effect of the AcrAB-TolC complex and nothing else [10].
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