An update on endotoxin neutralization strategies in Gram-negative bacterial infections

ABSTRACT

Introduction

Gram-negative bacterial infections represent still a severe problem of human health care, regarding the increase in multi-resistance against classical antibiotics and the lack of newly developed antimicrobials. For the fight against these germs, anti-infective agents must overcome and/or bind to the Gram-negative outer membrane consisting of a lipopolysaccharide (LPS, endotoxin) outer leaflet and an inner leaflet from phospholipids, with additional peripheral or integral membrane proteins (OMP’s).

Areas covered

The current article reviews data of existing therapeutic options and summarizes newer approaches for targeting and neutralizing endotoxins, ranging from in vitro over in vivo animal data to clinical applications by using databases such as Medline.

Expert opinion

Conventional antibiotic treatment of the bacteria leads to their killing, but not necessary LPS neutralization, which may be a severe problem in particular for the systemic pathway. This is the reason why there is an increasing number of therapeutic approaches, which – besides combating whole bacteria – at the same time try to neutralize endotoxin within or outside the bacterial cells mainly responsible for the high inflammation induction in Gram-negative species.

KEYWORDS:

• Lipopolysaccharide (endotoxin)
• LPS
• antimicrobial peptides
• anti-endotoxin immunoglobulin
• anti-endotoxin antibody
• toll-like receptor-4
• gram-negative infection
• inflammation
• endotoxemia
• sepsis

Article highlights

• LPS (Lipopolysaccharide, endotoxin) neutralization remains an unmet medical need.

• There are various approaches targeting the lipid A part of LPS, its ‘endotoxic principle’.

• The use of antimicrobial peptides (AMP) seems to be the most promising anti-sepsis therapy, in particular by applying polycationic compounds of suitable length and sufficient selectivity such as Aspidasept with an optimum therapeutic index. This approach seems to be most promising regarding also economic aspects.

• The application of monoclonal antibodies remains up to now unsuccessful due to the lack of broad-range binding to different LPS sero- and chemotypes.

• Animal models using only rodents have only limited predictive value, rabbit and pig models are more suitable since their immune systems are more similar to the human system.

• Clinical studies with the most promising new therapeutic approaches are still lacking.

Declaration of interest

K Brandenburg discloses a personal contract with Roche Diagnostics related to the Biophysics of LER. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

K Brandenburg acknowledges the financial support of the BMBF (Project “Therapy of infectious diseases with special regard to sepsis (01GUO924). WC that of the German Bundesministerium für Wirtschaft. Projects 1. Quantitativer Nachweis matrixassoziierter, antimikrobieller Peptide durch Massenspektrometrie ihrer Aminosäuren, No. ZF 4380902 NK7, 2.Calciumhaltige Implantatoberfläche mit antibakteriellen, antiinflammatorischen Wirkstoffdepots zur Vermeidung periprothetischer Infektionen. No KF 3382201 CS. G Martinez de Tejada acknowledges financial support from Proyectos de Investigación Universidad de Navarra, Spain (PIUNA-P2011-17 and P2015-14).