BUFFALO, N.Y. -- Antibiotic resistance results from bacteria's
uncanny ability to morph and adapt, outwitting pharmaceuticals that
are supposed to kill them. But exactly how the bacteria acquire and
spread that resistance inside individuals carrying them is not
well-established for most bacterial organisms.
Now, University at Buffalo microbiologists studying bacterial
colonization in mice have discovered how the very rapid and
efficient spread of antibiotic resistance works in the respiratory
pathogen, Streptococcus pneumoniae (also known as the
pneumococcus). The UB team found that resistance stems from the
transfer of DNA between bacterial strains in biofilms in the
nasopharynx, the area just behind the nose.
In a paper published in last month's mBio, the authors found
that genetic exchange of antibiotic resistance occurs about 10
million times more effectively in the nose than in the blood of
animals, an efficiency far higher than expected.
"The high efficiency of genetic transformation that we observed
between bacteria in the nose has a direct clinical implication,
since this is how antibiotic resistance spreads, and it's
increasing in the population," explains lead author Anders P.
Hakansson, PhD, assistant professor of microbiology and immunology
in the UB School of Medicine and Biomedical Sciences. "The bacteria
'borrow' each others' DNA in order to become more fit in the host
environment and more elusive to the actions of antibiotics."
Hakansson, who also is affiliated with the Witebsky Center for
Microbial Pathogenesis and Immunology and the New York State Center
of Excellence in Bioinformatics and Life Sciences, both at UB,
performed the study with co-authors Laura R. Marks, an MD/PhD
candidate, and Ryan M. Reddinger, a PhD candidate, both in the
Department of Microbiology and Immunology at UB.
Hakansson explains that the work has opened up a novel direction
into the mysteries of how bacteria organize during colonization and
how this organization promotes antibiotic spread and the
evolutionary fitness of Streptcoccus pneumoniae.
Streptococcus pneumoniae is a major colonizer: It's carried in
the nasopharynx by essentially everyone by about one year of age.
Only occasionally do people get sick from it, but often enough to
make it a leading cause of morbidity and mortality from respiratory
tract and invasive infections in children and the elderly
"It's rampant in daycare centers and the cause of many
childrens' ear infections," Hakansson says. "In developing
countries, where fresh water, nutrition and antibiotics are
lacking, it is a major cause of disseminating pneumonia leading to
sepsis and death of about a million children worldwide, often in
combination with virus infections, such as the flu."
The research exposes what Hakansson describes as the puzzling
history of studies into the transformation of genetic material
He explains that natural transformation or genetic exchange of
DNA in infected mice was first described in 1928 by Frederick
Griffith who was studying Streptococcus pneumoniae, because of its
role in the Spanish flu epidemic of 1918-1919. Genetic
transformation also helped identify DNA as the hereditary material
and thus figured in the milestone research of James D. Watson and
Francis Crick in determining the structure of DNA.
"Since then, all experiments with pneumococcal transformation
have been done artificially in test tubes or in blood infection
models," says Hakansson, "even though it's known epidemiologically
that genetic exchange occurs almost exclusively when the organism
exists in the nose.
"For some reason, no one had looked at how resistance spread in
the environment where it really happens, in the nasopharynx," he
continues." So we decided to do that. When we did, we found that
the efficiency with which antibiotics spread in the nasopharynx was
way above what we expected."
And last summer, the UB researchers published in Infection &
Immunity findings showing that when they colonize the nose,
pneumococci form sophisticated, highly structured biofilm
"We found that the bacteria make biofilms in the nose that
protect against the action of antibiotics, which have a hard time
destroying biofilms," says Hakansson. "In addition, we know that
some of the bacteria have to die in order to develop good biofilms.
So dead bacteria help create good biofilms and provide DNA that
other bacteria can take up and use, which is how bacteria spread
antibiotic resistance and become more fit."
The mBio paper shows that the environment in the nasopharynx
provides ideal conditions for these phenomena to occur.
"The temperature in the nose -- 34 degrees C, the epithelial
cells, the availability of nutrients -- all these factors are
creating ideal conditions for biofilm formation and the spread of
antibiotic resistance," says Marks.
The UB researchers reconstituted this environment in vitro by
growing bacterial biofilms on top of human bronchial carcinoma
cells or epithelial cells from healthy individuals provided by G.
Iyer Parameswaran, MD, research assistant professor of medicine at
UB and the Buffalo Veterans Affairs Medical Center.
The UB team is now working to develop clinical applications for
these findings with the goal of better treating and preventing
infections, especially with resistant organisms, from childrens'
ear infections to community and hospital-acquired pneumonia in the
elderly that can lead to lethal septicemia.
There is an increasing need, they note, to find ways to fight
antibiotic-resistant bugs: only about 15 antimicrobials are
currently in the development pipeline at the FDA.