Bacterial physiology and its role in antibiotic refractoriness

Abstract: The pathological outcome of a bacterial infection depends on the interplay among the host’s innate defenses, the virulence arsenal of the pathogen and antibiotic treatment strategies. Understanding this interplay will provide mechanistic insights on antibiotic pharmacodynamics and bacterial pathogenesis, and set the stage for the development of novel therapeutic interventions. The discovery and subsequent mass production of antibiotics has been one of the greatest achievements in medical history. Regardless of the fact that antibiotics have been used in medicine for more than 70 years, there is no clear mechanistic understanding of their effect on microbial populations in the host, and prediction of antibiotic pharmacodynamics is still complicated. In Paper I, we aimed to develop a simple model that links bacterial population biology and classical reaction kinetics, while rationally explaining complex patterns of antibiotic action (post-antibiotic growth suppression, density-dependent antibiotic effects, and persister cell formation). The emergence of antibiotic resistance along with the decline in the rate of discovery of new antibiotics has been one the major challenges in modern medicine. Multi-resistant strains (eg. methicillin resistant Staphylococcus aureus, MRSA) are responsible for infections with poor resolution and high mortality rates. The majority of the Staphylococci are commensal, however, they can be responsible for a variety of medical conditions caused by infection processes or the direct production of toxins (skin infections, deep tissue infections, toxic shock syndrome, septicemia, endocarditis). Treatment failure in Staphylococci has been associated with their ability to form biofilms, which have been implicated in chronic and recurring infections. Another physiological state that has been suggested to be of clinical importance is persister cells. Despite the lack of solid evidence on their clinical manifestation, persister cells have also been implicated in chronic infections. In Paper II, we aim to investigate the role of bacterial physiology in antibiotic refractoriness. We provided evidence of biofilm derivation for a significant fraction of persister cells. In Paper III, we investigated the effect of incubation atmosphere on the susceptibility of biofilm-derived cells and demonstrated an increased refractoriness of S. aureus biofilm-derived cells under anaerobic conditions. Polymicrobial communities play a major role in human health and disease. Recent studies have demonstrated that the gut microbiota modulates brain development and behavior. In Paper IV, we aim to investigate peptidoglycan sensing in the developing brain. In this study we provide solid evidence of a signaling pathway mediating the communication between the gut microbiota and the developing brain.