Medical Hypotheses 72 (2009) 250–251

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Antiresistance?
Lasse Nuotio *
Microbiology, Research Department, Finnish Food Safety Authority Evira, Mustialankatu 3, FI-00790 Helsinki, Finland

a r t i c l e i n f o s u m m a r y

Article history: After billions of years of evolution and untold numbers of bacterial generations there appears to be only a
Received 10 September 2008 finite number of genera belonging mainly to order Actinomycetales, producing largely similar types of
Accepted 25 September 2008 antibiotics all over the world. It is hypothesized that this not just a result of limited number of susceptible
targets or a transitory situation in the evolutionary process. It is proposed that there is some stabilizing
factor associated with the commonly encountered antibiotics that alleviates the selection pressure to
design new antibiotics. Synergistically acting molecules, an antibiotic and a component preventing the
action of resistance mechanism is one way to stabilise the situation; perhaps the best known example
of this is b-lactam antibiotics and clavulanic acid. However, it is considered possible that during the
extremely long evolution the Actinomycetes have also come up with metabolites preventing the actual
development of resistance. These kinds of compounds, used along with antibiotics, could perhaps signif-
icantly reduce the ever-increasing threat of resistance among pathogens. This appears to be an unex-
plored area.
Ó 2008 Elsevier Ltd. All rights reserved.

Introduction tions but are produced in nature and confer selective advantages
to the organisms that produce them [6,7].
The majority of present day antibiotics originate from a group of
ubiquitous gram-positive soil bacteria called Actinomycetes, and
A curious incident of evolution
especially from members of the genus Streptomyces [1,2]. These
antibiotics include tetracyclines, aminoglycosides and macrolides,
The evolution of bacteria and their primary and secondary
but also lincomycin, rifamycin, chloramphenicol and vancomycin,
metabolisms has been going on for a good 3.5 billion years. Taken
among others. The spectrum of bioactive compounds from the ver-
their relatively short generation times even in quite adverse condi-
satile ‘ray fungi’ includes also important antiparasitic drugs like
tions and the various ways of bacterial genome modifications and
avermectin, antifungals, antivirals, anticancer compounds, modu-
reorganisations, this time span must mean that every genetic com-
lators of immune system and a variety of other drugs useful in hu-
bination or permutation has been tried and selected for or against,
man medicine [1,3].
probably multiple times in the changing conditions of earth.
The antibiotics of especially the genus Streptomyces are typi-
Among other things this must mean that development of antibiotic
cally produced at the transition phase in colonial development
production and counterdevelopment or acquisition of means of
when the growth of the vegetative mycelium declines because of
resistance against them has been going on for an exceedingly long
nutrient exhaustion. Breakdown of the vegetative hyphae releases
time. It is probably reasonable to assume that the development of
nutrients usable in the development of aerial mycelium [4]. The
measures and their countermeasures take place in cycles so that
production of antibiotics is usually considered to belong to the cat-
once the genetic machineries and the metabolic expenses they in-
egory ‘secondary metabolism’, that is, the products are nonessen-
cur become obsolete, they are of necessity dropped.
tial for growth but otherwise useful for the producing organism.
Yet we know that in every gram of fertile soil there are probably
Safeguarding the nutrients from competitors for the aerial myce-
tens if not hundreds of strains of Actinomytetes. Many of them are
lium would be one obvious task. The earlier common view that
able to produce at least weakly active antibiotic compounds, most
the secondary metabolites were either neutral in evolutionary
of which if isolated and characterized would turn out to be ver-
terms or useful only in somehow idling the metabolic machinery
sions of already known antibiotics. Producers of for example carba-
has been convincingly refuted [5]. It is now appreciated that sec-
penems have been isolated from all over the world [1]. This very
ondary metabolites are not artifacts of laboratory culture condi-
situation, ubiquitous existence of soil bacteria belonging to only
a finite number of genera and producing similar kinds of antibiotic
* Corresponding author. Tel.: +358 9 02077 24453. metabolites after billions of years of evolution and untold numbers
E-mail address: lasse.nuotio@evira.fi of bacterial generations, begs for an explanation.

0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.09.041
 L. Nuotio / Medical Hypotheses 72 (2009) 250–251
The road not taken
The obvious explanation is of course, that there is but a limited
number of susceptible targets in the constitution of the potential
competitors. However, does the present number of frequently
encountered or even of all the known antibiotics really reflect
the total number of good targets? This must be something that
at the present state of knowledge of bacterial physiology, metabo-
lism and molecular biology, to say nothing about the composition
of the competitive bacterial floras in different types of soil, is
impossible to conclude with any certainty. Another ready explana-
tion would be that this is just a transitional state of affairs. The
competitors are commissioning resistance genes from the original
antibiotics producers and honing these or alternative countermea-
sures of their own, even as we speak. After a suitable time span,
evolutionarily speaking, the antibiotics we have found will proba-
bly be replaced with others. Quite possibly, after another suitable
time span evolution has returned to some of the present day anti-
biotics since the number of possible targets, even if large and also
evolving, probably is limited in the end.
However, it is also possible that the production of those antibi-
otics we frequently have encountered is somehow stabilized so
that their evolution is, if anything, very much slower than would
otherwise be expected. The putative stabilizing factor can for
example be one able to prevent or restrict the action of the resis-
tance molecule(s) or mechanism(s). There are in fact numerous
examples of the production by an actinomycete of two chemically
different metabolites that act either synergistically against a target
microorganism, or contingently to overcome competition for nutri-
ents. Perhaps the best known example of the synergistic action is
that of b-lactam antibiotics and clavulanic acid. The latter is a nat-
ural inhibitor of b-lactamase enzymes, which confer resistance to
the b-lactams (such as penicillin) in many microorganisms. There
are also other known synergistically acting metabolites [7] and
most likely more will be found if searched for. A highly desirable
property of the synergistically acting metabolite would be that it
does not readily induce some kind of resistance to itself.
Yet another intriguing if only slight possibility is that the anti-
biotic producing organisms have evolved also metabolites that
effectively prevent not the action of the developed resistance
mechanism but the very development of the resistance. A number
of the unusually large genomes (for eubacteria) of Streptomyces
have been sequenced but the characterization of the genes is very
far from complete. For example S. griseus (a recognized producer
of streptomycin) contains 34 gene clusters or genes for the
biosynthesis of known or unknown secondary metabolites [8].
Production of some kind of ‘antiresistance’ metabolite(s) could
be one or even several of the unknowns. The immensity of the
resistance-associated genetic diversity of streptomycetes was
demonstrated by D’Costa et al. [9] who found several previously
251
uncharacterized mechanisms and resistance even against fully
synthetic antibiotics among the 480 actinomycete-resembling
strains studied. Considering the common view that only a fraction
of soil-dwelling organisms have ever been cultivated and studied
in the laboratory, the potential of finding novel types of bioactive
compounds is tangible. It must be noted that the schematized
antiresistance molecules would not necessarily have to be very
complex. For example acylated tripeptides were found to selec-
tively cleave the D-Ala–D-Lac termini from the peptidoglycan pre-
cursors of vancomycin resistant enterococci (VRE) re-sensitizing
the bacteria to vancomycin [10]. These kinds of metabolites
would effectively keep the nearby development of resistant clones
at bay.
Resistance to antibiotics among pathogenic bacteria is a serious
problem nowadays and one not likely to be won by trying to stay a
step ahead of the pathogens with ever new antibiotics. Means to
reduce or possibly to completely prevent the development or
selection of resistant clones during treatments would be of great
value in keeping the trusted and safe antimicrobial therapies effec-
tive. Despite the obvious benefits it appears that no systematic
searches for the sketched antiresistance metabolites have been
conducted. This may of course be a false impression; the negative
results have just not been published. However, for example the
comprehensive colloquium paper of Challis and Hopwood [7],
although discussing the b-lactam antibiotics/clavulanic acid and
other examples of synergism and contingent action of metabolites
at length, does not consider even a theoretical possibility for
metabolites having effect on the actual development of resistance.
The road may thus indeed be untaken.
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