Multiple in two ways, first by up regulation

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Multiple drug resistance (MDR) can be correlated to a variable
mechanisms, including synthesis of enzymes that degrade the drugs, non-responding
modified targets and presence of efflux pumps that pump out the antibacterial
drugs from the bacterial cells to the extracellular environment. Scientist have
found that QS regulate MDR in two ways, first by up regulation of biofilm
associated extracellular
polymeric substance (EPS) matrix and second by up regulation of
efflux pump genes. The synthesis of an EPS matrix is one of the essential characteristics
of biofilm and it has been noted that EPS inhibits the access of antibiotics
into the bacterial community. The investigators reveal that there is an
important association between MDR and biofilms. As an example, in the majority
of clinical isolates of Acinetobacter baumannii, that were strong producers
of biofilm were also exhibiting MDR. Biofilm producers
isolates, compared to non-biofilm producers, showed a significantly higher
resistance to ciprofloxacin, amikacin, aztreonam and cephotaxime. Additional
studies showed the importance of antibiotic resistant determinant blaPER-1 for
cell adherence, that represent the initial step in the formation cycle of
biofilm. What make Acinetobacter a strong and resistant bacteria specie
is its ability to hold stressful conditions like the exposure to high
antibiotic concentrations.

Other studies on Pseudomonas have mentioned that the biofilm
formation is enhanced once bacterial cells were exposed to the macrolide
antibiotics. Thus, suggesting that biofilm formation
act as a potential defense mechanism against antibiotics. QS molecules play a
“Chef d’Orchestre” role in antibiotic resistance, due to their ability to
enhance plasmids replication and transfer, that are the major genes carriers of
antibiotic resistance. Further studies for the QS role in the upregulation of
efflux pumps in E. coli have shown that the overexpression of SdiA, the E.
coli luxR homologue, results to the over expression of AcrAB efflux pumps
and the knockdown of SdiA leads to the downexpression of AcrAB gene. Additionally, SdiA regulates cell division with a cell
density-dependent manner. Combined with previous research works, these results
reveal the role of drug efflux pumps is the mediation of intercellular
communication related to cell density .

Another example for efflux regulation by QS molecules, is the MexR
repressor downregulation of mexAB-oprM efflux pump expression in P.
aeruginosa, once the cells are in the logarithmic phase, this regulation
occurs by the binding to the MexR-MexABOprM operator-promoter region. When the
cells are in the stationary phase, they sense an increase in the cells density
that lead to the activation of a QS switch by producing C4-HSL as an
autoinducer, that directly induces the expression of mexAB-oprM operon or
inhibit the activation of the MexR repressor, therefore the transcription of
MexAB-oprM efflux pump is enhanced .

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Antibiotic resistance in A. baumannii is also related to efflux
pump and RND efflux genes, that show 47% of similarity with the MexAB pumps, it
should be noted that in in A. baumannii, MexAB pumps represent the major
efflux pumps in this specie. In addition, the QS molecules C12-HSL  produced by A. baumannii, may have a
connection with efflux pumps that induce MDR. As a response to stress conditions, bacterial cells express
different molecular factors to overcome the non-favorable situation. One of the
major factor is the sigma factor RpoS regulated by the RNA chaperone Hfq.
Investigators studying P. aeruginosa have shown that lasR knockout
mutants were less resistant to ofloxacin, and this resistance was restored once
they overexpress RpoS in lasR knockouts. Since Hfq has
a regulation role on RpoS that is highly involved as a key factor of QS and
antibiotic resistance controle, thus the important relation between signal
molecules during stressful conditions in QS and MDR. Genomic analyses of Acinetobacter,
that show the interconnection role of Hfq and RpoS in A. baumannii are
not yet clear. Therefore, innovative antimicrobials with novel modes of action
are urgently required. One alternative approach is targeting the bacterial QS.

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