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Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae.

ABSTRACT: Phage lysins constitute a new generation of antimicrobials that are becoming a promising alternative and complementation to current antibiotic therapies, which are nowadays called into question by the increasing numbers of multiresistant bacteria. Streptococcus pneumoniae is a leading human pathogen causing serious infectious diseases in children and adults. Within the host-parasite interplay system of pneumococcus and its phages, several antipneumococcal lysins have been described and, among them, chimeric lysins Cpl-711 and PL3 stand out for their potent bactericidal activities. Here, evidence is presented on the synergistic cooperation of the catalytically diverse lysins Cpl-711 and PL3 in different assays, like purified cell wall enzymatic degradation, in vitro bacterial cell growth inhibition, and killing of both planktonic and biofilm grown cells. Synergy between Cpl-711 and PL3 has been shown to reduce the amount of enzyme necessary to inhibit growth in checkerboard assays with a sum of fractional inhibitory concentrations ?0.5 for all pneumococcal strains tested, while also significatively increasing bactericidal effect by ?2 logs with respect to the sum of activities of Cpl-711 and PL3 individual treatments. Moreover, the combination of these two lysins showed synergy in an adult zebrafish model of pneumococcal infection. This study consolidates the possibility of formulating highly efficient and synergistic antibacterial enzymes that could improve our ability to fight multiresistant bacterial infections.

SUBMITTER: Vazquez R

PROVIDER: S-EPMC6560164 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Synergy Between Two Chimeric Lysins to Kill <i>Streptococcus pneumoniae</i>.

Vázquez Roberto R García Pedro P

Frontiers in microbiology 20190605

Phage lysins constitute a new generation of antimicrobials that are becoming a promising alternative and complementation to current antibiotic therapies, which are nowadays called into question by the increasing numbers of multiresistant bacteria. <i>Streptococcus pneumoniae</i> is a leading human pathogen causing serious infectious diseases in children and adults. Within the host-parasite interplay system of pneumococcus and its phages, several antipneumococcal lysins have been described and, a ...[more]

PMID: 31231338

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Project description:Streptococcus pneumoniae rapidly kills Staphylococcus aureus by producing membrane-permeable hydrogen peroxide (H2O2). The mechanism by which S. pneumoniae-produced H2O2 mediates S. aureus killing was investigated. An in vitro model that mimicked S. pneumoniae-S. aureus contact during colonization of the nasopharynx demonstrated that S. aureus killing required outcompeting densities of S. pneumoniae Compared to the wild-type strain, isogenic S. pneumoniae ΔlctO and S. pneumoniae ΔspxB, both deficient in production of H2O2, required increased density to kill S. aureus While residual H2O2 activity produced by single mutants was sufficient to eradicate S. aureus, an S. pneumoniae ΔspxB ΔlctO double mutant was unable to kill S. aureus A collection of 20 diverse methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains showed linear sensitivity (R2 = 0.95) for S. pneumoniae killing, but the same strains had different susceptibilities when challenged with pure H2O2 (5 mM). There was no association between the S. aureus clonal complex and sensitivity to either S. pneumoniae or H2O2 To kill S. aureus, S. pneumoniae produced ∼180 μM H2O2 within 4 h of incubation, while the killing-defective S. pneumoniae ΔspxB and S. pneumoniae ΔspxB ΔlctO mutants produced undetectable levels. Remarkably, a sublethal dose (1 mM) of pure H2O2 incubated with S. pneumoniae ΔspxB eradicated diverse S. aureus strains, suggesting that S. pneumoniae bacteria may facilitate conversion of H2O2 to a hydroxyl radical (·OH). Accordingly, S. aureus killing was completely blocked by incubation with scavengers of ·OH radicals, dimethyl sulfoxide (Me2SO), thiourea, or sodium salicylate. The ·OH was detected in S. pneumoniae cells by spin trapping and electron paramagnetic resonance. Therefore, S. pneumoniae produces H2O2, which is rapidly converted to a more potent oxidant, hydroxyl radicals, to rapidly intoxicate S. aureus strains.IMPORTANCEStreptococcus pneumoniae strains produce hydrogen peroxide (H2O2) to kill bacteria in the upper airways, including pathogenic Staphylococcus aureus strains. The targets of S. pneumoniae-produced H2O2 have not been discovered, in part because of a lack of knowledge about the underlying molecular mechanism. We demonstrated that an increased density of S. pneumoniae kills S. aureus by means of H2O2 produced by two enzymes, SpxB and LctO. We discovered that SpxB/LctO-produced H2O2 is converted into a hydroxyl radical (·OH) that rapidly intoxicates and kills S. aureus We successfully inhibited the toxicity of ·OH with three different scavengers and detected ·OH in the supernatant. The target(s) of the hydroxyl radicals represents a new alternative for the development of antimicrobials against S. aureus infections.

Dataset Information

Synergy Between Two Chimeric Lysins to Kill Streptococcus pneumoniae.

Publications

Synergy Between Two Chimeric Lysins to Kill <i>Streptococcus pneumoniae</i>.

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