Scientists find Potential Weapon against Antibiotic Resistance
Resistance to antibiotics by bacteria and other microbes is an ongoing public health crisis, contributing to about two million infections and 23,000 deaths per year in the United States, according to the Centers for Disease Control and Prevention. P. aeruginosa, for instance, is a multidrug-resistant pathogen associated with hospital-acquired infections, including ventilator-associated pneumonia. As for S. aureus, some strains do not cause disease. Others cause the classic “staph” infections that antibiotics do kill. Other strains, though, are antibiotic-resistant.
Staphylococcus aureus is responsible for numerous chronic and relapsing infections such as osteomyelitis, endocarditis, and infections of the cystic fibrosis (CF) lung, as well as many penetrating trauma and burn infections, venous leg ulcers, pressure ulcers, and diabetic foot ulcers.
These infections are notoriously difficult to treat, despite isolates frequently exhibiting full sensitivity to administered antibiotics, as measured in vitro using a Minimum Inhibitory Concentration (MIC) assay. This suggests that environmental factors present in vivo may influence the pathogen’s susceptibility to antibiotic killing.
Similarly, within complex polymicrobial communities such as those encountered in chronic skin infections, burn wound infections, and chronic colonization of the CF lung, inter- and intraspecies interactions can influence the pathogenicity and antibiotic susceptibility of
individual organisms. The presence of the fungal pathogen Candida albicans, for instance, can induce S. aureus biofilm formation and thus decrease the bacterium’s susceptibility to antibiotic killing.Furthermore, antibiotic deactivation by resistant organisms within a population can lead to de facto resistance of all members of the community.
In such polymicrobial infections, S. aureus is commonly co-isolated with the opportunistic pathogen Pseudomonas aeruginosa. These co-infections are generally more virulent and/or more difficult to treat than infections caused by either pathogen alone.
The interaction between these 2 organisms is complex, with P. aeruginosa producing a number of molecules that interfere with S. aureus growth, metabolism, and cellular homeostasis.
Now, in a new study led by Brian P. Conlon, PhD, assistant professor of microbiology and immunology at the University of North Carolina at Chapel Hill, the team hypothesized that interaction with P. aeruginosa may antagonize or potentiate S. aureus antibiotic susceptibility and could explain the frequent occurrence of treatment failure in infections involving otherwise drug-susceptible strains. Furthermore, they also hypothesized that such interactions could be exploited to improve antibiotic treatment outcome.
“The interactions with P. aeruginosa can completely change S. aureus’s susceptibility to standard antibiotics,” said study senior author Brian P. Conlon, PhD, assistant professor of microbiology and immunology at UNC.
“We know that P. aeruginosa commonly co-infects with S. aureus and secretes factors that mess with S. aureus’s metabolism,” Conlon said. “So our hypothesis was that this interaction might be throwing S. aureus into a more antibiotic-resistant state.”
Conlon and colleagues uncovered that S. aureus sometimes adopts a slow-growing, “low-energy” state that makes it more difficult to kill with antibiotics. The team hypothesized that this low-energy state might arise from inter-species competition. In other words, a co-infecting bacterial species might have evolved the capability to produce factors that put microbial competitors at a disadvantage. Such factors may include toxins, enzymes, or various bacterial components unique to specific strains.
They set up a panel of S. aureus cultures, exposed them to molecules secreted by 14 different P. aeruginosa strains, and then tested the susceptibility of each culture to one of three antibiotics: vancomycin, tobramycin, and ciprofloxacin. The results were striking and have implications for clinical practice.
The P. aeruginosa factors affected S. aureus’s susceptibility to all three antibiotics, in some cases to an enormous extent. Some strains of P. aeruginosa, as expected, significantly reduced S. aureus’s susceptibility to tobramycin and ciprofloxacin. Surprisingly, though, many other strains of P. aeruginosa greatly enhanced S. aureus’s susceptibility to antibiotics used in the experiments.
“Factors secreted by eight of the P. aeruginosa strains, for example, induced 100 to 1000 times more killing of S. aureus by vancomycin, compared to the control culture of S. aureus that was not exposed to P. aeruginosa factors,” Conlon said.
The researchers believe that it could be possible to create new antibiotics that include the susceptibility-enhancing factors LasA and rhamnolipids – and/or block the susceptibility-reducing factor HQNO – to build a better arsenal against serious bacterial infections.
The team is now sequencing P. aeruginosa strains to see how gene sequences vary between strains and how this variance affects the ability of these strains to produce the aforementioned factors Conlon’s lab has described.
