Novel and structurally diverse beta-lactam - beta-lactamase inhibitor (BL-BLI) combinations displaying activity against multi-drug resistant (MDR) Gram-negative bacteria have recently become available including ceftazidime-avibactam, ceftolozane-tazobactam and meropenem-vaborbactam. Despite their limited use, resistance to the BL-BLI has already been described. The CO-PROTECT project aims to (i) systematically evaluate the epidemiology of resistance development against BL-BLI in MDR E. coli, K. pneumoniae and P. aeruginosa and dissect their mechanisms incl. genome sequencing and –omics approaches; (ii) investigate addition of several combination partner antibiotics active against MDR in order to protect BL-BLI against resistance development exploiting synergy, evolutionary selective disadvantage and collateral sensitivity incl. the dissection of the combined mode of action; and (iii) establish a translational framework comprising state-of-the-art hollow-fiber experiments, innovatively designed in vivo animal studies and pharmacokinetic-pharmacodynamic modelling and simulations. Hence, CO-PROTECT will identify favorable combination regimens (high efficacy, low selection of resistance) that are implementable off the shelve in the clinical setting. Moreover, CO-PROTECT will generate an innovative research platform that can be applied to further research investigating combination therapies.