Elucidando a resistência a combinação de amicacina e polimixina B em Klebsiella pneumoniae

Abstract

Klebsiella pneumoniae infections have been a major concern in public health due to their high levels of mortality and resistance leading to the necessity for the development of new treatments. Trying to anticipate the resistance development, this study evaluated resistance to amikacin plus polymyxin B combination in K. pneumoniae. High levels of resistance were achieved by subinhibitory combination therapy of amikacin and polymyxin B evolutionary in vitro model. This resistance showed stability for 10 days without selective pressure and fitness cost were associated with two of the three resistant lineages. Cross-resistance was also observed to colistin and some antimicrobial peptides. Moreover, genomics analysis of the resistant strains showed a diversity of mutated genes related to different kinds of resistance mechanisms such as lipopolysaccharides modification and expression (lapB and phoP), aminoglycosides modification (alphA), and oxidative stress resistance (rho). Further, differential gene expressions analysis showed different kind of resistance response as capsule production (rcsC), binding inhibition of antibiotics with their targets (lpxT and pseudouridine synthase), repair damage from stress response (degP, ligB), and capture polymyxin in the periplasm (opgH). Among all, the latter appears to be a promising unexplored target for future therapies.