Microbial Evolution and Co-Adaptation A Tribute to the Life and Scientific Legacies of Joshua Lederberg: Workshop Summary (2009) / Chapter Skim
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4 Antibiotic Resistance: Origins and Countermeasures
4 Antibiotic Resistance: Origins and Countermeasures
Pages 158-192
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From page 158... ...
As Stanley Cohen of Stanford University observes in his contribution to this chapter, "It seems quite remarkable that despite the enormous progress made in the treatment of infectious disease during Joshua Lederberg's lifetime, the ominous microbial threat discussed by Lederberg on multiple occasions continues." The papers collected in this chapter explore the evolutionary origins of the antibiotic resistance phenomenon, take its measure as a present and future threat to public health, and propose scientific approaches to addressing it, including investigating environmental reservoirs of antibiotic resistance, identifying sources of novel antibiotics, and developing alternatives to conventional antibiotic therapies. In the chapter's first paper, workshop speaker Julian Davies, of the University of British Columbia, reviews the history of the development of antibiotic resistance, beginning in the early twentieth century.
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From page 159... ...
Cohen describes the strategy by which he and coworkers have identified several such pathogen-exploited host genes and discusses their prospects as therapeutic targets. "There is hope that devising antimicrobial therapies that target host cell genes exploited by pathogens, rather than -- or in addition to -- targeting the pathogens themselves may help in the effort to thwart the microbial threat," he concludes.
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From page 160... ...
ANTIBIOTIC RESISTANCE AND THE FUTURE OF ANTIBIOTICS Julian Davies, Ph.D.1 University of British Columbia Naturally occurring small molecules, and their synthetic and semisynthetic derivatives, have been used as the foundation of infectious disease therapy since the late 1930s. Following the introduction of the "wonder drugs" penicillin and streptomycin, dozens of novel and derived bioactive compounds have been developed and used for the treatment of microbial maladies in humans, animals, and plants.
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From page 161... ...
, CTX-M resistant Escherichia coli and Klebsiella pneumoniae, Clostridium dif 3 MRSA is a type of S aureus that is resistant to antibiotics called β-lactams.
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Occasionally, structurally novel compounds have been isolated that offer a narrow window of therapeutic success, but this has become less common and there is no panacea yet. Given the seriousness of the current situation, a number of well-considered proposals have been mooted with the objective of controlling resistance development and restoring and maintaining the efficacy of treatments against infectious diseases (Norrby et al., 2005; Spellberg et al., 2008)
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From page 163... ...
as origins of extended-spectrum β-lactamases 2001 Identification of gyrA allelism in soil isolates that provides such isolates with "natural" fluoroquinolone resistance 2004 Identification of resistance genes in the soil metagenome 2006 Identification of the environmental "resistome" that conveys multidrug resistance in soil isolates 2006 Identification of the "intrinsic" resistome of pathogens (gene knockouts) 2008 Identification of the environmental "subsistome" -- a population of bacteria that degrades antibiotics voir of resistance genes to be acquired by bacterial pathogens.
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From page 164... ...
Cryptic resistance genes that are present in bacteria or bacterial populations may be revealed by metagenomic cloning and expression (Riesenfeld et al., 2004) , although it will be necessary to employ a wide range of expression hosts, in addition to E
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From page 165... ...
However, the acquisition process is not well understood, and essentially all aspects of the origins and evolution of antibiotic resistance genes remain unsolved. Integron-encoded gene cassettes are widespread in all natural environments (marine and terrestrial)
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From page 166... ...
are also hotspots, with significant concentrations of antibiotic-resistant microbes containing multiple resistance genes from a wide variety of antibiotics and myriad potential vectors. That WWTPs provide ideal environments for gene exchange and gene acquisition has been confirmed by studies of antibiotic resistance plasmids isolated from WWTP bacterial cultures (Tennstedt et al., 2005)
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From page 167... ...
We have proposed that these hormetic effects of antibiotics account for the differences in activity of low-molecular-weight compounds in their natural environment (soils, etc.) compared to their role in the treatment of infectious diseases.
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From page 168... ...
On the contrary, it is well known that most of the antimicrobial agents used therapeutically do not kill other bacteria -- they only inhibit the growth of the target organism. This is an important aspect of antimicrobial therapy: the drug retards or inhibits bacterial growth and virulence and allows the human immune system to eliminate the weakened pathogens.10 The Global Microbiome Bacteria are the most abundant living organisms on this planet and, given that they are essential to the maintenance of all other living organisms, they are 10 For this reason, treatment with compounds with a cidal action is favored for patients who are immunosuppressed or in cases of critical infections caused by highly virulent organisms.
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From page 169... ...
Based on estimates of the putative small molecule biosynthetic clusters predicted from the nucleotide sequences of bacterial genomes, most soil and other environmental microbes have the genetic capacity to produce a number of bioactive compounds that are active at very low concentrations. Since many soil bacteria have the capacity to produce up to 20 different bioactive compounds, the notion of community structures controlled by small molecules becomes obvious.
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From page 170... ...
, a collection of bacteria isolated from the 1920s (the Murray Collection) were found to carry plasmids, but no resistance genes; a number of the plasmids were shown to be transferable by conjugation.
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From page 171... ...
Their discovery was essentially the result of human intervention, the consequence of a laboratory phenomenon that developed into an industry. Unfortunately, although antibiotic production and use have been of enormous medical and commercial value in transforming the therapy of infectious diseases in the last 60 years, the extensive use of antimicrobial agents during this period has not led to the eradication of any one bacterial pathogen.
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From page 172... ...
Surely governments, the pharmaceutical industry, and academia can cooperate in actions that will curtail resistance development in pathogens and support efforts to provide a continuing supply of potent antimicrobial agents. Such a concerted effort is urgent.
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In the 1870s, Louis Pasteur and Robert Koch first advanced the germ theory, which focused on the causal role of microbes in infectious disease. Half a century later, Griffith (1928)
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Multidrugresistant bacteria were observed first in Japan in the late 1950s and soon were detected also in other countries throughout the world. Multidrug-resistant bacteria quickly emerged as a medical problem because the drug resistance genes they carry could pass horizontally via conjugation to other bacteria -- some of which were more pathogenic than the original plasmid host -- as well as linearly to the progeny of the resistant cells.
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From page 175... ...
Similarly, the effects of microbial toxins are also dependent on host functions: anthrax toxicity, for example, requires the recruitment of host proteins to enable uptake and processing of the toxin, as shown in Figure 4-4. When I raise the prospect of developing antimicrobial therapies that target host cell functions recruited by pathogens, there typically are questions about whether interference with such host functions will result in unacceptable drug toxicity.
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From page 176... ...
Finding host genes recruited by pathogens is practical using gene inactivation approaches. However, as mammalian cells normally contain two copies of each gene, inactivation of both copies ordinarily is necessary to produce biological effects.
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From page 177... ...
. The biological effects of gene inactivation observed during Chromosomal allele containing GSV GSV Chromosomal transcript Regulated antisense promoter Chromosomal transcript Chromosomal allele lacking GSV FIGURE 4-5 Diagrammatic representation of the site of chromosomal insertion of a Figure 4-5.eps lentiviral GSV.
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CGEPs Identified Using Gene Inactivation Approaches The first gene isolated by the RHKO strategy -- tumor susceptibility gene 101 (Tsg101) -- was identified using a tumor susceptibility screen (Li and Cohen, 1996)
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From page 179... ...
Conclusion It seems quite remarkable that despite the enormous progress made in the treatment of infectious diseases during Joshua Lederberg's lifetime, the ominous microbial threat discussed by Lederberg on multiple occasions continues. A simple fact underlies this threat: for every pathogen-encoded protein or nucleic acid targeted by a therapeutic agent, there is the potential for a target-altering mutation that can render the therapy ineffective.
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From page 180... ...
I will begin with a brief overview of our work on the discovery of antibiotic resistance genes in communities of soil bacteria, and proceed to a more detailed discussion of a model system that we have developed to study endogenous microbial communities and their role in host health and disease. 15An agency of the U.S.
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From page 181... ...
Some clones contain gene sequences resembling those of known resistance genes from clinical isolates; these genes express enzymes (such as β-lactamases, pencillinases, and carbapenemases) that degrade β-lactam antibiotics.
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From page 182... ...
We study the role of microorganisms in communities that inhabit the midguts of gypsy moth and cabbage white butterfly larvae. These are good model systems, as the larvae are easy to rear and dissect and their gut microbial communities can be readily and naturally manipulated via host feeding.
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From page 183... ...
Quorum sensing is mediated by small molecules called homoserine lactones. Some thought it was impossible that these molecules -- and therefore quo TABLE 4-3 Phylogeny of Cultured and Uncultured Bacteria from Third Instar Gypsy Moth Midguts Feeding on an Artificial Diet Phylotype Division Genus Species 1a low G+C gram positive Enterococcus spp.
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Image Min = −1.8561e+05 Max = 84991 p/sec/cm 2 /sr 10,000 9,000 8,000 7,000 6,000 5,000 4,000 FIGURE 4-6 Detection of quorum-sensing activity and signal exchange in the guts of Figure 4-6 COLOR.eps cabbage white butterfly larvae. Bioluminescence was detected in the individual guts of larvae fed Pantoea pSB401image w/ antoea mixed with Pantoea panI::Tn pSB401 bitmap (top row)
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From page 185... ...
60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 Days After Inoculation FIGURE 4-7 Mortality of cabbage white butterfly larvae fed P aeruginosa strains and the Figure 4-7.eps quorum-sensing analog indole inhibitor.
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From page 186... ...
As a result, she developed the hypothesis that the gut microbial community acts as a protection -- a phalanx -- against infection by Bt, and she predicted that eliminating the gut bacteria would enhance Bt activity. To test this hypothesis, we treated insects with increasing concentrations of an antibiotic cocktail that we knew would kill all of the bacteria that we could detect in the gut (Broderick et al., 2006)
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. led us to the traitor hypothesis: if Bt is inactive in the absence of the endogenous microbial community, then perhaps community members actually collaborate with Bt in a multispecies infection.
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This system might provide a model for studying the common phenomenon that commensal microbes can act as pathogens under the right conditions. The insect gut system and the soil metagenomic analysis of antibiotic resistance genes both reveal the importance of accounting for communities in the analysis of microbial behavior and genetic potential in biological systems.
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2004. Uncultured soil bacteria are a reservoir of new antibiotic resistance genes.
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2008. Recruitment of the TSG101/ESCRT-1 machinery in host cells by influenza virus: implications for broad spectrum therapy.
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2008. Quorum sensing signals in the microbial community of the cabbage white butterfly larval midgut.
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2004. Census of the bacterial com munity of the gypsy moth larval midgut by using culturing and culture-independent methods.
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