Antibiotic‐dependent perturbations of extended spectrum beta‐lactamase producing Klebsiella pneumoniae proteome

Extended spectrum beta‐lactamase producing Klebsiella pneumoniae (ESBL‐KP) causes life‐threatening infections in susceptible and immuno‐compromised individuals. Because of the emergence of multidrug resistance and tolerance, it is crucial to better understand the mechanisms by which ESBL‐KP can adapt to antibiotic stress. The aim of this study was to provide an overview of the global proteome changes occurring in ESBL‐KP in response to sub‐lethal concentrations of the antibiotics doxycycline (DC, bacteriostatic) and streptomycin (SM, bactericidal), which both impair ribosomal synthesis of bacterial proteins. These results represent the greatest experimental coverage of the ESBL‐KP proteome yet described. The 1538 proteins, representing 30% of the 5126 predicted KP gene products were identified from the combined experimental groups. Antibiotic stress resulted in significantly elevated levels of 42 proteins for DC and 55 for SM treatments, whereas 53 proteins were reduced for DC‐ and six for SM‐treated bacteria. Specifically, the ESBL‐KP response to DC was accompanied by the reduced levels of the porins LamB, CirA, FepA, and OmpC. In contrast to DC, the stress response to SM demonstrated a dramatic increase in the peroxidase detoxification pathway proteins PutA, KatG, KatE, and Dps, which prevent harmful hydroxyl radical formation. The results from this proteomic study are important for understanding adaptive responses to antibiotics, and may provide novel targets for the development of new therapeutic strategies.