Nisin-associated-sensitivity-response-regulator (NsaRS) in Staphylococcus aureus is important for its adhesion to surfaces and resistance against antibiotics, like nisin. NsaRS consists of an intra-membrane-located sensor NsaS and a cytoplasmatically-located response-regulator NsaR, which becomes activated upon receiving phosphate groups from the intratmembrane-located sensor. Hypothesis: The intra-membrane location of the NsaS sensor leads us to hypothesize that the two component NsaRS system not only senses "chemical" (nisin) but also "mechanical" (adhesion) stresses to modulate efflux of antibiotics from the cytoplasm. Experiments: NsaS sensor and NsaAB efflux pump transcript levels in S. aureus SH1000 adhering to surfaces exerting different adhesion forces were compared, in presence and absence of nisin. Adhesion forces were measured using single-bacterial contact probe atomic force microscopy. Findings: Gene expression became largest when staphylococci experienced strong adhesion forces combined with nisin-presence and the two-component NsaRS response to antibiotics was enhanced at a stronger adhesion force. This confirms that the intra-membrane-located sensor NsaS senses both chemical and mechanical stresses to modulate antibiotic clearance through the NsaAB efflux pump. This finding creates better understanding of the antibiotic resistance of bacteria adhering to surfaces and, in the fight against antibiotic-resistant pathogens, may aid development of advanced biomaterials on which bacterial efflux pumps are not activated. (C) 2017 Elsevier Inc. All rights reserved.