Affiliation:
1. Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Abstract
ABSTRACT
Staphylococcus aureus
is a significant cause of infections worldwide and is able to utilize aerobic respiration, anaerobic respiration, or fermentation as the means by which it generates the energy needed for proliferation. Aerobic respiration is supported by heme-dependent terminal oxidases that catalyze the final step of aerobic respiration, the reduction of O
2
to H
2
O. An inability to respire forces bacteria to generate energy via fermentation, resulting in reduced growth. Elucidating the roles of these energy-generating pathways during colonization of the host could uncover attractive therapeutic targets. Consistent with this idea, we report that inhibiting aerobic respiration by inactivating heme biosynthesis significantly impairs the ability of
S. aureus
to colonize the host. Two heme-dependent terminal oxidases support aerobic respiration of
S. aureus
, implying that the staphylococcal respiratory chain is branched. Systemic infection with
S. aureus
mutants limited to a single terminal oxidase results in an organ-specific colonization defect, resulting in reduced bacterial burdens in either the liver or the heart. Finally, inhibition of aerobic respiration can be achieved by exposing
S. aureus
to noniron heme analogues. These data provide evidence that aerobic respiration plays a major role in
S. aureus
colonization of the host and that this energy-generating process is a viable therapeutic target.
IMPORTANCE
Staphylococcus aureus
poses a significant threat to public health as antibiotic-resistant isolates of this pathogen continue to emerge. Our understanding of the energy-generating processes that allow
S. aureus
to proliferate within the host is incomplete. Host-derived heme is the preferred source of nutrient iron during infection; however,
S. aureus
can synthesize heme
de novo
and use it to facilitate aerobic respiration. We demonstrate that
S. aureus
heme biosynthesis powers a branched aerobic respiratory chain composed of two terminal oxidases. The importance of having two terminal oxidases is demonstrated by the finding that each plays an essential role in colonizing distinct organs during systemic infection. Additionally, this process can be targeted by small-molecule heme analogues called noniron protoporphyrins. This study serves to demonstrate that heme biosynthesis supports two terminal oxidases that are required for aerobic respiration and are also essential for
S. aureus
pathogenesis.
Publisher
American Society for Microbiology
Cited by
113 articles.
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