Staphylococcus aureus: What Makes It So Nasty…and Successful?

“In severe cases, staph spreads beyond the skin and becomes life-threatening. Resistant strains such as [Methicillin-resistant Staphylococcus aureus] turn what should be a treatable infection into a medical nightmare.”

Linda Stewart, News and Current Affairs Editor, The Microbiologist

“Staphylococcus aureus bacteremia is a leading cause of infection-related death worldwide…Yet, there is a critical need to establish safe and effective treatment regimens that also offer convenience and other attributes important to patients and their families.”

Eric McCreary, PharmD, Journal of American Medical Association, August 13, 2025

If you exclude Mycobacterium tuberculosis, Staphylococcus aureus is the number one cause of death from bacterial pathogens globally. It’s no wonder that all clinicians have a very healthy fear of this pathogen.

In this week’s Germ Gems post, I discuss what makes S. aureus such a formidable enemy and mention a new antibiotic (dalbavancin) that looks promising as treatment of one of the most feared bacterial infections, S. aureus bacteremia.

What is Staphylococcus aureus? Staphylococcus aureus is a Gram-positive spherically shaped bacterium and is a common member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin.  Its name is derived from the Greek words staphyle (“bunch of grapes”), kokkus (“berry”), and aureus for the golden-yellow colonies on an agar plate. Alexander Ogden, a Scottish surgeon, discovered the bacterium in 1880.

S. aureus usually acts as a commensal (without causing harm) of the human microbiota. But it can also become an opportunistic pathogen causing skin and respiratory infections.  It harbors a variety of virulence factors, including toxins, such as toxic shock syndrome toxin-1 (the cause of toxic shock syndrome), exfoliative toxins (responsible for staphylococcal scalded skin syndrome), and several others.

What kinds of infections does S. aureus cause? S. aureus is the leading cause of surgical wound infections. (It is therefore not all that surprising that a surgeon discovered the bacterium.) It is also a common cause of skin (cellulitis) and soft tissue infections. Additionally, S. aureus can infect the lungs (pneumonia), heart valves (endocarditis), and brain (meningitis and abscesses). S. aureus attracts neutrophils, which can form abscesses (pockets of pus) in a variety of organs. (In addition to the epithelial barrier of the skin, neutrophils, antibodies, and complement are the most important host defenses against S. aureus.)

S. aureus is the most feared cause of bloodstream infections (bacteremia). The overall mortality of S. aureus bacteremia is about 25%.  One of the worst complications of bacteremia is endocarditis (infection of one or more heart valves)—a complication that is uniformly fatal if untreated. Because of this potential complication, when I was teaching, I suggested to medical students that whenever the microbiology laboratory called to report that a blood culture from their patient was positive for S. aureus, their first response should be “Oh S###” (aka as the “Staph aureus oh s### reflex”) as this is the only bacterium with such a high predilection for infecting heart valves.

Antibiotic treatment and resistance. Prior to the 1940s, many S. aureus infections were routinely fatal. This changed dramatically after Alexander Fleming discovered the antibiotic penicillin in 1928.

Fleming found that S. aureus cultures when contaminated with a mold (later identified as Penicillium notatum) developed a clear zone where the bacterium could not grow. This demonstrated penicillin’s antibacterial properties. Penicillin subsequently cured patients with many life-threatening staphylococcal infections.

In 1945, Fleming, Howard Florey and Ernst Chain were awarded the Nobel Prize in Physiology or Medicine for the discovery of penicillin. In his acceptance speech, Fleming cautioned that the public demand for penicillin could result in its overuse and misuse and could lead to antibiotic resistance. His warning was prescient.

S. aureus’s ubiquity and virulence contribute importantly to its nasty profile. But I believe this bacterium’s ability to evolve clever mechanisms to resist antibiotic activity is the leading feature of its nastiness.

Penicillin-resistance was first detected in 1947 and by1948 penicillin-resistance was widespread in hospitals. Similarly, methicillin, a beta-lactam antibiotic related to penicillin, was introduced into clinical practice in 1959.  Less than a year later, methicillin-resistant S. aureus (MRSA) appeared in many hospitals and then in the community. And this has been going on for the past seven decades—pharmaceutical companies chasing antibiotic resistance of MRSA by developing ever new antibiotics.

Dalbavancin is one of the more recently developed antibiotics that is active against MRSA. On August 13, 2025, researchers published the results of a randomized clinical trial of this long-acting lipoglycopeptide. (Turner, N., et al., “Dalbavancin for Treatment of Staphylococcus aureus Bacteremia,” Journal of American Medical Association, August 13, 2025).  The trial included 200 adults with complicated S. aureus bacteremia who received either 2 doses of intravenous dalbavancin or 4 to 8 weeks of daily doses of a standard intravenous antibiotic.

Dalbavancin was not found to be superior to the standard regimens at achieving the desirable outcome (clearance of the bloodstream infection). Nonetheless, the convenience of only two intravenous administrations versus 4 to 8 weeks of daily dosing support an important role of dalbavancin in the treatment of S. aureus bacteremia.

Why we’re stuck with S. aureus. No one knows for sure how long S. aureus has been around. But, it has been referred to as a “successful parasite.” (Mudd, S. [Ed.], Infectious Agents and Host Reactions, W.B. Saunders Co., 1970). And, it was only recently that researchers discovered a new feature that promotes S. aureus’s success.

Researchers at Auburn University’s Physics Department along with researchers in the United Kingdom and Belgium showed that S. aureus hooks onto human skin with the strongest biological grip ever measured, stronger than Super Glue and nearly unmatched in nature. (Chantraine, C,  et al., “Ultrastong staphylococcus aureus adhesion to human skin: Calcium as a key regulator of noncovalent interactions,” Science Advances, September 3, 2025; see also, Stewart, L. ““The cling of doom: how Staph bacteria latch onto human skin,” EurekaAlert, September 2025). This discovery helps explain why S. aureus remains attached to the skin even after scratching, sweating, or washing.

At the center of this discovery is a bacterial protein called SdrD, which S. aureus uses like a grappling hook to attach itself to a human protein called desmoglein-1. The bond between the two is unlike anything seen before. It withstands forces so powerful that they rival the strength of some chemical bonds.

According to Rafael Bernardi, an Associate Professor of Physics at Auburn University and one of the senior authors of the study, “It is the strongest non-covalent protein-protein bond ever reported…This is what makes staph so persistent and helps us understand why these infections are so difficult to get rid of.”

Some scientists may admire the strong attachment S. aureus has to us humans. But the hope of most researchers is that this discovery leads to a clever way to sever our ties with this nasty and “successful parasite.”