Post antibiotic treatment expansion of pathogenic microbes Wenfa Ng figshare 18 Dec 2016.pdf (222.4 kB)
Post antibiotic treatment expansion of pathogenic gut microbes induced by availability of oxidised sugars
Development of resistance to antibiotics treatment is
a concept familiar to scientists and the general public through frequent news
reports and feature articles in the popular media. In general a phenomenon
where bacteria enter into a quiescent state known as persistence or a metabolic
program called stringent response, or through acquisition of genetic repertoire
conferring resistance to antibiotics, it came about usually through the non
completion of a course of antibiotic treatment, where subpopulations of
bacteria that survive the initial rounds of treatment are able to obtain
nutrients more effectively due to lack of competition from other vulnerable
microbial species vanquished by antibiotics. However, possibility exists where
certain strains of bacteria may harbour resistance genes capable of countering
the effects of antibiotics through a combination of efflux pumps or mutation of
original drug target, which can therefore survive a completed course of
antibiotic treatment. Not restricted to either broad spectrum or narrow
spectrum antibiotics treatment, such populations of bacteria, however small in
numbers at the start, could expand into the dominant species of a microhabitat
in the body, and portends significant risk to the host if it is a pathogenic
strain. Known as post-antibiotic treatment expansion of pathogenic species, the
issue holds significant implications to the design of antibiotics, selection of
potential drug targets to reduce chances of evolution of resistance, and the
tailoring of antibiotic treatment to the individual in terms of both drug
combinations, sequence of antibiotic administration, and duration of treatment.
Tackling the question in a hypothesis driven manner, Baumler and coworkers examined
the host factors that indirectly facilitated an expansion of a pathogenic
strain of Salmonella Typhimurium in
research reported in “Host-mediated sugar oxidation promotes post-antibiotic
pathogen expansion”, Link.
Specifically, the researchers hypothesized that greater availability of
oxidized sugars such as aldehydes and alcohols could provide increased
nutrients allowing the proliferation of pathogenic S. Typhimurium in the gut of mouse after antibiotic treatment.
Using a gene construct encoding proteins important to the import of
galactarate, recombinant S.
Typhimurium was constructed, and uptake of oxidized glucose (i.e., glucarate)
and oxidized galactose (i.e., galactarate) followed by their subsequent
fermentation is confirmed. But, where does the oxidizing power for glucarate
and galactarate comes from? The authors answered through animal model research
where they showed through gas chromatography mass spectrometry that reactive
nitrogen species released by inducible nitric oxide synthase (iNOS) of mouse
most likely oxidized glucose into glucarate; thereby, presenting the gut
microbiota with a selection pressure that favours the growth of pathogenic S. Typhimurium able to uptake and
ferment glucarate. Inhibition of iNOS through addition of inhibitors was
observed to significantly dent the population expansion of S. Typhimurium, which highlights the essentiality of glucarate and
galactarate uptake and fermentation in conferring a fitness advantage to the
pathogenic species. Thus, the research outlines a mechanism whereby antibiotic
treatment could lead to elevated reactive nitrogen species in the gut that
alters the nutritional balance in a way that favours pathogenic species over
commensal ones. However, the critical link between why antibiotic could
activate nitric oxide synthase signalling pathway in the host remains
mechanistically unknown. Solving it could provide important details on the
selection of specific type of antibiotics that would not result in a cascade of
events that lead to post antibiotic treatment expansion of dangerous pathogens
that could permanently alter the dynamics of the gut microbiota. Collectively,
the reported research opens microbiologists’ eyes to how a benign and
efficacious antibiotic such as streptomycin could potentiate an expansion of a
resident pathogenic strain of Salmonella
sp. through induction of an important host broad spectrum signalling cascade,
that results in greater quantities of a metabolite that only the pathogenic and
drug resistant strains could ferment; thereby, yielding a population expansion
that changed gut microbiota dynamics.