The identification of genomic biomarkers is a key step towards improving diagnostic tests and therapies. We present a new reference-free method for this task that relies on a k-mer representation of genomes and a machine learning algorithm that produces intelligible models. The method is computationally scalable and well-suited for whole genome sequencing studies. The method was validated by generating models that predict the antibiotic resistance of C. difficile, M. tuberculosis, P. aeruginosa, and S. pneumoniae. We show that the obtained models are accurate and that they highlight biologically relevant biomarkers, while providing insight into the process of antibiotic resistance acquisition.