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Title: Antibiotic Resistance as a Stress Response

Speaker: Catarina Milheiriço

Affiliation: Hermínia Lencastre Lab, ITQB NOVA

Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most significant multi-resistant pathogens worldwide. Methicillin resistance is the most relevant clinical resistance trait acquired by S. aureus, since it confers resistance to virtually all beta-lactam antibiotics, the most commonly prescribed class of antibiotics. Methicillin is no longer produced due to its side effects; oxacillin replaced it in susceptibility testing, but the original term MRSA is still used to describe β-lactam resistant strains.

The central determinant of methicillin resistance – the mecA gene – is carried in a mobile genetic element of heterologous origin – the Staphylococcal Cassette Chromosome mec (SCCmec) and encodes an extra penicillin-binding protein (PBP2A) with low affinity to virtually all β-lactam antibiotics, which allows cell wall synthesis to continue even in the presence of β-lactams. MRSA show extensive strain-to-strain variation in the oxacillin Minimum Inhibitory Concentration (MIC), the mechanism of which is not well understood. Moreover, most MRSA strains exhibit a heterogeneous phenotype of beta-lactam resistance under routine growth conditions, where the majority of cells exhibit low level of resistance, but subpopulations of seemingly isogenic bacteria exhibiting high-levels of resistance are also present with variable frequencies. This phenotype can have considerable clinical relevance since upon challenge with beta-lactam agents, a highly resistant subpopulation may rapidly be selected from a heterogeneously resistant MRSA population.

The studies I am going to present were developed in order to better understand the mechanism of heterogeneous resistance phenotype to oxacillin in MRSA. Several MRSA bacterial lineages have been tested and the data achieved so far point for the involvement of the stringent stress response in the establishment of high-levels of oxacillin resistance among the minority subpopulations present in the MRSA populations with heteroresistance phenotype.