Antibiotic-resistant bacteria can share resources to cause chronic infections, Vanderbilt investigators have discovered. Like the individual members of a gang who might be relatively harmless alone, they turn deadly when they get together with their ‘friends.’ The findings, reported in Cell Host & Microbe, shed light on a long-standing question in infectious diseases and may inform new treatment strategies.
One way that Staphylococcus aureus and other pathogens can become resistant to antibiotics is by changing the way they generate energy and becoming small colony variants, which are small and weak. The question has been, how do bacteria that are less fit and grow poorly in the laboratory cause such persistent infections in humans?
The current studies support the notion that antibiotic-resistant staph bacteria, including methicillin-resistant (MRSA) strains, can exchange nutrients with each other and even with other bacterial species, including the ‘normal’ microbes of the microbiome, to increase their virulence during an infection. The findings challenge infectious disease dogma.
The thinking has been that if an infection becomes resistant to antibiotics, then the resistant organisms appeared clonally, meaning they’re all genetically the same. The team wondered if perhaps instead there are a bunch of organisms that became resistant in different ways and that can exchange the molecules they’re each individually missing.
The researchers tested this hypothesis by mixing together two different small colony variant strains of staph, one that can’t produce heme and the other that can’t make menaquinone. They found that in culture, these strains exchanged the two metabolites and grew as if they were wild-type staph.
Next, they tested the idea in a mouse model of bone infection (osteomyelitis). Antibiotic-resistant small colony variant S. aureus is the cause of chronic and difficult to treat osteomyelitis and also of lung infections in patients with cystic fibrosis (CF). The investigators demonstrated that either staph strain alone (heme- or menaquinone-deficient) caused only minimal bone infection, but mixed together, they caused a fully virulent and bone-destroying infection. In bone, these bacteria were observed trading molecules.
The researchers then isolated samples of staph small colony variants and normal bacteria from the lungs of CF patients. When individual CF staph small colony variants were mixed together in culture, they grew like wild-type bacteria. Likewise, co-culture of CF staph small colony variants with normal microbiome bacterial species also enhanced the growth of staph in culture. The microbiome of a cystic fibrosis patient’s lungs can provide nutrients to these small colony variants and revert them to wild-type behaviour.
The findings show that these antibiotic-resistant infections are not what the medical community thought they were, they’re not a single strain of bacteria with a single lesion leading to the small colony variant phenotype. Instead, they’re a mixed population of organisms that are sharing nutrients. They act like a big group of bullies until they’re hit with drugs, then they stop sharing resources and are resistant. When the drugs go away, they start sharing resources again and get even tougher.
The researchers state that they are now a little bit smarter about how these organisms are behaving in an infection, which the team think they can use to inform new treatment approaches.
Preventing the nutrient exchange, for example, may offer a new therapeutic strategy against these antibiotic-resistant organisms.
Source: Vanderbilt University
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