Bacterial defenses undermine promising antibiotic combo strategy
A new study reveals why experimental treatments combining colistin with advanced antibiotics fail against drug-resistant bacteria: the microbes simply thicken their outer walls to block the drugs. The finding explains conflicting trial results and could reshape how pharmaceutical companies design the next generation of infection treatments.
Originaltitel: Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against ESBL- and carbapenemase-producing <em>Klebsiella pneumoniae</em>
<p>Combinations of colistin and beta-lactam/beta-lactamase inhibitors (BLBLIs) have shown in vitro synergy against beta-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against beta-lactamase-producing Klebsiella pneumoniae. Genetically modified strains were constructed by introducing bla(CTX-M-15), bla(KPC-2), and bla(OXA-48) chromosomally into K. pneumoniae ATCC 35657, in which the major porin-encoding genes (ompK35, ompK36) were either intact or knocked out. The in vitro activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the beta-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the beta-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the beta-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.</p>