Recalcitrant Staphylococcus aureus Infections: Obstacles and Solutions

Abstract

Antibiotic treatment failure of Staphylococcus aureus infections is very common. In addition to genetically encoded mechanisms of antibiotic resistance, numerous additional factors limit the efficacy of antibiotics in vivo. Identifying and removing the barriers to antibiotic efficacy is of major importance as even if new antibiotics become available, they will likely face the same barriers to efficacy as their predecessors. One major obstacle to antibiotic efficacy is the proficiency of S. aureus to enter a physiological state that is incompatible with antibiotic killing. Multiple pathways leading to antibiotic tolerance and the formation of tolerant sub-populations called persister cells, have been described for S. aureus. Additionally, S. aureus is a versatile pathogen that can infect numerous tissues and invade a variety of cell types, some of which are poorly penetrable to antibiotics. It is therefore unlikely that there will be a single solution to the problem of recalcitrant S. aureus infection. Instead, specific approaches may be required to target tolerant cells within different niches, be it through direct targeting of persister cells, sensitization of persisters to conventional antibiotics, improved penetration of antibiotics to particular niches or any combination thereof. Here we examine two well described reservoirs of antibiotic tolerant S. aureus, the biofilm and the macrophage, the barriers these environments present to antibiotic efficacy and potential solutions to the problem.

Convergent Evolution of Antibiotic Tolerance in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

“…Additionally, oxidative stress may reduce TCA cycle flux through destruction of the iron-sulfur clusters of key TCA cycle enzymes ( 54 ), causing antibiotic tolerance independently of any DNA coding changes. Furthermore, low TCA cycle flux is associated with a reduction in the proton motive force (PMF) across bacterial membranes, and some antibiotics depend on PMF for entry into cells in order to be active ( 55 ). Antibiotic tolerance can also be induced within phagocytic cells that have internalized S. aureus ( 54 , 56 ), and these internalized bacteria may represent a reservoir for relapsing and persistent S. aureus infections.…”

Host Polyunsaturated Fatty Acids Potentiate Aminoglycoside Killing of Staphylococcus aureus

“…Aminoglycoside antibiotics rely on the proton motive force (PMF) to enter the cell ( 2 ). As a facultative anaerobe, S. aureus obviates the need for PMF by generating energy through fermentation, leading to persisters that are tolerant of but not resistant to aminoglycosides ( 3 – 6 ). Fermenting S. aureus requires higher concentrations of aminoglycosides to eradicate infection, but these elevated concentrations lead to host nephrotoxicity and ototoxicity ( 7 – 9 ).…”

“… S. aureus persister cell formation is characterized by a shift in metabolism from respiration to fermentation, collapse of the PMF, and tolerance of aminoglycosides ( 3 – 6 ). Consistent with this, infections caused by S. aureus strains that are respiration deficient due to genetic mutations or small colony variants (SCVs) are notoriously difficult to treat with antibiotics, including aminoglycosides ( 21 – 24 ).…”

The giant staphylococcal protein Embp facilitates colonization of surfaces through Velcro-like attachment to fibrillated fibronectin

“…Bacteria in the biofilm evade phagocytosis by immune cells (3), and the immune system can therefore not eradicate the infections. Furthermore, a fraction of the cells enter a dormant state in which they are highly tolerant to antibiotics (4). With the rise in use of biomedical implants, there is an urgent and growing need to understand how biofilm infections arise, such that new strategies for preventative treatment can be developed.…”