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Neutralizing Virulence

Characteristics that distinguish disease-causing pathogens from the benign commensal microbes of our normal flora are known as "virulence factors". Examples of virulence factors include toxins that damage host tissues or impair cellular function, adhesins and invasins that help the pathogen colonize and spread within the host, resistance factors that impair immune clearance, and molecules that can provoke excessive harmful inflammation.  


Don't Destroy, Disarm

Traditional antibiotics are chemicals identified based on their ability to efficiently kill or block the growth of microbes in a test tube. In response to the life-or-death challenge of antibiotic selection, pathogens are increasing evolving resistance to the important first and second line drugs we rely upon in the clinics. CHARM Investigators are exploring a novel approach to infectious disease therapy: targeting key virulence factors to strip pathogens of their virulence. In this drug discovery model, the concept is to render the pathogen harmless and easily cleared by our natural defenses.

Help Preserve a Healthy Microbiome

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One important advantage of targeting virulence to treat infectious diseases is the potential to reduce harmful effects on the normal microbiota. Most current antibiotics prescribed in medicine have broad-spectrum activity, meaning that in addition to treating the pathogenic infection, they also inadvertently kill off many "innocent bystanders" among the beneficial bacteria living in our gut, skin and other mucosal surfaces. Repeated loss of beneficial microbes can predispose to medical complications such as Clostridium difficile colitis and vaginal yeast infections, and increases the risk of allergic diseases and metabolic disorders. In contrast, anti-virulence therapies target specific molecules of individual pathogen, avoiding damage to the patient's microbiome.

Opportunities and Challenges

CHARM investigators are evaluating drugs that prevent pathogens from producing key virulence factors, and others that neutralize the factor after it is made (e.g. by a monoclonal antibody). Virulence factor inhibitors are unlikely to be cross-resistant to existing therapies, less likely to select for resistance themselves, and may serve as adjunctive therapy alongside existing antibiotics or as potentiators of the host immune response. Members of this new class of infectious disease therapeutics are likely to be narrow spectrum and will require a new testing paradigm to assess their potency.

 

A Wolf in Sheep's Clothing

Group B Streptococcus (GBS), a leading cause of sepsis and meningitis in human newborns, is not killed by platelets. The GBS polysaccharide capsule that coats the bacterial surface and contains sialic acid (Sia), a common sugar present on all human cells. CHARM Investigators showed this "molecular mimicry" blocks platelet antimicrobial factors and engages an inhibitory receptor (Siglec-9) to block platelet activation.

Read the article in PNAS