It may be time to re-think the antibiotic. Traditional antibiotics act by killing the infecting organism, much the way an army would seek to do to it’s enemies. But if an army could somehow disarm its foes, taking away every last weapon, wouldn’t that accomplish the same end? The authors of a study in mBio this week took a similar approach to treating infections: they allowed the invading bacteria to live, but disabled the toxin the bacteria use to attack the body, healing the disease even though the bacteria were still present in high numbers. The results may herald the dawn of a new type of antibiotic drugs – medicines that disarm pathogens but don’t kill them.
New drugs are badly needed for treating infections with the bacterium Acinetobacter baumannii, a pathogen that most often strikes hospital patients and immune compromised individuals through open wounds, breathing tubes, or catheters. Strains of A. baumannii have acquired resistance to a wide range of antibiotics, and pan-drug resistant (PDR) A. baumannii infections are resistant to every FDA-approved antibiotic, making them untreatable.
Co-author Brad Spellberg of the UCLA Medical Center and the David Geffen School of Medicine at UCLA says he and his coworkers found the key to the bacterium’s vulnerability when comparing the ability of different strains to kill mice. “We found that strains that caused the rapidly lethal infections shed lipopolysaccharide [also called LPS or endotoxin] while growing. The more endotoxin shed, the more virulent the strain was,” says Spellberg. This pinpointed a new therapy target for the researchers: the LPS these bacteria shed in the body.
Spellberg says LPS works by stimulating a component of the immune system called toll-like receptor 4 (TLR4), a type of molecule that acts like the body’s Paul Revere, alerting the immune system to the presence of invading organisms and setting off a cascade of reactions in the body. Mice that lack the receptor TLR4 are not susceptible to A. baumanii infections, indicating that it is the interaction between the bacterium’s LPS and the body’s TLR4 that kills, not just the LPS.
What if you could shut off the LPS, preventing it from interacting with the body’s TLR4? The researchers tested whether shutting down the synthesis of LPS with a small molecule called LpxC-1 would prevent infected mice from getting sick.
It worked. Unlike traditional antibiotics, Spellberg says, LpxC-1 doesn’t kill the bacteria, it just shuts down the manufacture of LPS and stops TLR4 and the body from mounting the inflammatory response that so often kills seriously ill patients.
Spellberg says this is a direction few researchers have taken when exploring ways to treat infections, but that it could make the difference in finding an effective drug. “The way we screen for antibiotics can be myopic. Traditionally, people have tried to find antibiotics that rapidly kill bacteria. But we found a new class of antibiotics which has no ability to kill Acinetobacter that can still protect, not by killing the bug, but by completely preventing it from turning on host inflammation.” Gram negative bacterial pathogens use LPS as a virulence factor, says Spellberg, and it may make more sense to treat those infections by stopping the bacteria from making LPS rather than trying to kill every last pathogen in the body.
The results also highlight how important it is to find new, physiologically-relevant ways of screening potential antibiotics for pathogens with a high degree of resistance, write the authors, since molecules like LpxC-1 wouldn’t pass muster with traditional killing-effectiveness screens.
Liise-anne Pirofski of the Albert Einstein College of Medicine edited the study for mBio. Pirofski says neutralizing virulence factors is showing a lot of promise as an alternative route for treating infections. “There’s a growing movement in infectious disease therapy to control the host inflammation response in treatment rather than just ‘murdering’ the organism,” says Pirofski. “This is a very elegant and important validation that this approach can work – at least in mice.”