Pseudomonas aeruginosa is a highly
antibiotic-resistant opportunistic pathogenic bacteria that is responsible
for thousands of deaths each year. Infections with P. aeruginosa disproportionately impact individuals
with compromised immune systems as well as cystic fibrosis patients,
where P. aeruginosa lung infection
is a leading cause of morbidity and mortality. In previous work, we
showed that a combination of gallium (Ga) nitrate and Ga protoporphyrin
worked well in several bacterial infection models but its mechanism
of action (MOA) is unknown. In the current work, we have investigated
the MOA of Ga combination therapy in P. aeruginosa and its analysis in the in vivo model. In P. aeruginosa treated with Ga combination therapy,
we saw a decrease in catalase and superoxide dismutase (SOD) activity,
key antioxidant enzymes, which could correlate with a higher potential
for oxidative stress. Consistent with this hypothesis, we found that,
following combination therapy, P. aeruginosa demonstrated higher levels of reactive oxygen species, as measured
using the redox-sensitive fluorescent probe, H2DCFDA. We also saw
that the Ga combination therapy killed phagocytosed bacteria inside
macrophages in vitro. The therapy with low dose was
able to fully prevent mortality in a murine model of P. aeruginosa lung infection and also significantly
reduced lung damage. These results support our previous data that
Ga combination therapy acts synergistically to kill P. aeruginosa, and we now show that this may occur
through increasing the organism’s susceptibility to oxidative
stress. Ga combination therapy also showed itself to be effective
at treating infection in a murine pulmonary-infection model.
The treatment of infections is becoming
more difficult due to emerging
resistance of pathogens to existing drugs. As such, alternative druggable
targets, particularly those that are essential for microbe viability
and thus make it harder to develop resistance, are desperately needed.
In turn, once identified, safe and effective agents that disrupt these
targets must be developed. Microbial acquisition and use of iron is
a promising novel target for antimicrobial drug development. In this
Review we look at the various facets of iron metabolism critical to
human infection with pathogenic microbes and the various ways in which
it can be targeted, altered, disrupted, and taken advantage of to
halt or eliminate microbial infections. Although a variety of agents
will be touched upon, the primary focus will be on the potential use
of one or more gallium complexes as a new class of antimicrobial agents. In vitro and in vivo data on the activity
of gallium complexes against a variety of pathogens including ESKAPE
pathogens, mycobacteria, emerging viruses, and fungi will be discussed
in detail, as well as pharmacokinetics, novel formulations and delivery
approaches, and early human clinical results.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.