Abstract
Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. An important player of the immune system is the complement system, a protein network in serum that directly kills Gram-negative bacteria through pore-formation by the Membrane Attack Complexes (MAC). We here show that the MAC rapidly perforates the outer membrane but that inner membrane damage, which is essential for killing, is relatively slow. Importantly, we demonstrate that MAC-induced outer membrane damage sensitizes Gram-negative bacteria to otherwise ineffective, Gram-positive-specific, antimicrobials. Synergy between serum and nisin was observed for 22 out of 53 tested Gram-negative clinical isolates and for multi-drug resistant (MDR) blood isolates. The in vivo relevance of this process is further highlighted by the fact that blood sensitizes a MDR K. pneumoniae strain to vancomycin. Altogether, these data imply that antibiotics that are considered ineffective to treat infections with Gram-negatives may have different functional outcomes in patients, due to the presence of the complement system.
Highlights
Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane
We show for the first time that complement sensitizes a broad range of clinical isolates to antibiotics that are currently considered ineffective for treatment of Gram-negative bacteria
Complement-mediated outer membrane damage is more efficient than inner membrane damage
Summary
Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. We show for the first time that complement sensitizes a broad range of clinical isolates (including MDR strains) to antibiotics that are currently considered ineffective for treatment of Gram-negative bacteria. In order to study how the MAC kills bacteria, we used a flow cytometry based assay to measure serum-induced outer and inner membrane damage in E.
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