Artemisinin and Nitric Oxide Mechanisms and Implications in Disease and Health

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It can be concluded that ART facilitates the bactericidal effect of antibiotics by
synchronously inactivating bNOS and CAT, which provide a cost-effective strat-
egy against lethal bacterial infections (Zeng et al. 2011 ). The development of more
potent antibiotics should prohibit the lethal pathogens from worldwide transmis-
sion, but it is costly, time consuming, and technically difficult (Patel and Crane
2010 ). If an antibiotic synergist like ART could be beneficial to antibiotics for
fighting bacteria, it would minimize the antibiotic dosage and cost. Importantly,
antibacteria with antibiotics and synergists should impede the rapid incidence and
transmission of MDR bacteria.

5.2.4 Conclusions

Oxidative stress-acclimatized bacteria were found to thrive in the presence of RIF
by generating NO, which was evident from accelerated bacterial growth under
RIF, but can be repressed by ART or l-NMMA. Suppressed bacterial prolifera-
tion was found to correlate with mitigated NO production upon the combination
of ART with RIF/CEF. The detection of ART-heme conjugates and accordingly
declined bNOS and CAT activities indicated that ART renders bacteria susceptible
to antibiotics by alkylating hemoproteins. By compromising NO-mediated protec-
tion from antibiotics and triggering harmful H 2 O 2 burst, ART serves as a promis-
ing antibiotic synergist for killing MDR bacteria.

4.3 In Vivo Evaluation on ART as a Synergist

of Antibiotics Against Bacterial Infection

5.2.1 Purposes and Significance

Although some antibiotics and toxins might lead to bacterial DNA damage and
cell death due to the induction of oxidative stress, bacteria can survive through
the cytoprotective effect mediated by NO. Such effects are integrated from (1)
direct detoxification; (2) CAT activation; (3) SOD induction, and (4) a suppressed
Fenton reaction (Gusarov et al. 2009 ). In the in vitro test, we gained a partial sup-
porting result regarding ART synergistic to antibiotics. For further evaluating the
sensitization of antibiotics by ART in vivo, we combined ART with some com-
monly used antibiotics for antibacterial tests in mice.
As mentioned earlier, the G+ bacterium B. Licheniformis should carry bNOS,
so ART would inhibit its NO production. In contrast, the G− bacterium E. coli
should not possess bNOS, so ART cannot affect its NO production. Nevertheless,
it is worthy of noting that mouse gastrointestinal tract is an extraordinarily com-
plex organ because there has an interaction of gut microbiota with intestinal
mucosa cells. First, not only bacteria produce the protective NO, but also host

4.2 In Vitro Examination for ART Suppressing ...