MicrobiologyBytes

UK scientists had an important role to play in the development of the first antibiotics for the treatment of tuberculosis in the mid-20th century. As we enter the second decade of the 21st century, the world is now confronted with the appearance of extremely drug-resistant strains. In this article in Microbiology Today (pdf) Stephen Gillespie asks what are UK scientists doing this time to help combat this serious threat?

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“We live in an era in which we depend on antibiotics, and other antimicrobial medicines to treat conditions that decades ago, or even a few years ago in the case of HIV/AIDS, would have proved fatal. When antimicrobial resistance – also known as drug resistance – occurs, it renders these medicines ineffective. For World Health Day 2011, WHO will be calling for intensified global commitment to safeguard these medicines for future generations. Antimicrobial resistance – the theme of World Health Day 2011, 7 April 2011 – and its global spread, threatens the continued effectiveness of many medicines used today to treat infectious diseases. For World Health Day 2011, WHO will call on governments and stakeholders to implement the policies and practices needed to prevent and counter the emergence of highly resistant microorganisms.”

via WHO | World Health Day – 7 April 2011

Recognized as a global problem, antibiotic resistance increases the morbidity and mortality caused by bacterial infections, as well as the cost of treating infectious diseases. The threat from resistance (particularly multiple resistance in bacterial strains that are widely disseminated) is serious. The key factors contributing to this threat are the pressure of increased antibiotic usage (in both human and animal medicine), greater mobility of the population and industrialization. Many potentially life-threatening infections, generally regarded as diseases from the past due to the success of antibiotics and vaccines, have returned as resistance increasingly hampers successful therapy and prophylaxis.

Several studies have focused on antibiotic resistance codification in plasmids or transposons, and there is also interesting information about the extent of antibiotic resistance genes in a given environment (the so-called “resistome”). However, there is less information on the potential contribution of phages to antibiotic resistance-gene transfer, despite calls for research in this field. Recent reports conclude that the horizontal transfer of genetic information by phages is much more prevalent than previously thought, and that the environment plays a crucial role in the phage-mediated transfer of antibiotic-resistance genes. This paper highlights the potential role of phages in the spread of these genes in the aquatic environment.

Antibiotic Resistance Genes in the Bacteriophage DNA Fraction of Environmental Samples. (2011) PLoS ONE 6(3): e17549. doi:10.1371/journal.pone.0017549
Antibiotic resistance is an increasing global problem resulting from the pressure of antibiotic usage, greater mobility of the population, and industrialization. Many antibiotic resistance genes are believed to have originated in microorganisms in the environment, and to have been transferred to other bacteria through mobile genetic elements. Among others, β-lactam antibiotics show clinical efficacy and low toxicity, and they are thus widely used as antimicrobials. Resistance to β-lactam antibiotics is conferred by β-lactamase genes and penicillin-binding proteins, which are chromosomal- or plasmid-encoded, although there is little information available on the contribution of other mobile genetic elements, such as phages. This study is focused on three genes that confer resistance to β-lactam antibiotics, namely two β-lactamase genes (blaTEM and blaCTX-M9) and one encoding a penicillin-binding protein (mecA) in bacteriophage DNA isolated from environmental water samples. The three genes were quantified in the DNA isolated from bacteriophages collected from 30 urban sewage and river water samples, using quantitative PCR amplification. All three genes were detected in the DNA of phages from all the samples tested, in some cases reaching 104 gene copies (GC) of blaTEM or 102 GC of blaCTX-M and mecA. These values are consistent with the amount of fecal pollution in the sample, except for mecA, which showed a higher number of copies in river water samples than in urban sewage. The bla genes from phage DNA were transferred by electroporation to sensitive host bacteria, which became resistant to ampicillin. blaTEM and blaCTX were detected in the DNA of the resistant clones after transfection. This study indicates that phages are reservoirs of resistance genes in the environment.

It is eye-opening to search the internet for the term MRSA (methicillin-resistant Staphylococcus aureus) these days. Instead of epidemiological treatises from Morbidity and Mortality Weekly Report, or reports of decreasing surgical site infections attributed to the advent of active surveillance followed by decolonization and contact isolation procedures, one finds that the first items that are highlighted link to Michael Jackson’s nose infection following another of his minor rhinoplastic touch-ups; a web page devoted to the new best-seller wannabe, Maryn McKenna’s book Superbug, The Fatal Menace of MRSA; and recently World MRSA Day (October 2nd, in case your laboratory wishes to have an event) sponsored by the MRSA Survivors’ Network. Yes, MRSA has celebrity spokespersons, in the shape of actors Tanner Richie and Alicia Cole. How did this microbe, only a few years older than HIV, become so infamous? Actually, we have ourselves partly to blame…

MRSA: a case of pathogens, politics and penalties. Trends Microbiol. 23 Feb 2011
In the current era of public scientific ‘debate’ such as the scientific merit of climate change, it should come as no surprise that a bacterium would have its 15 minutes of political limelight. Furthermore, a few dedicated citizens can truly influence the lives of many by changing the law of the land. For microbiologists, who often complain that our contributions go unnoticed and that we have no political power, this story serves to prove otherwise.

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Clustering of MRSA strains across Europe
• Staphylococcus aureus: superbug

Antibiotics can have ecological effects that impact the efficacy of other antimicrobial agents or facilitate the development of secondary infections. When antibiotics are administered, particularly when they are overused or misused, they change the environment and the biome, which in turn can lead to the selection or development of bacterial strains resistant to a wide range of antibiotic agents, extending beyond the particular antibiotic or antibiotic class initially administered. Certain antibiotic agents also change the normal bacterial flora or environment within the gastrointestinal tract, which in turn can promote the colonization and overgrowth of particular bacteria (e.g. Clostridium difficile), and increase the risk of gastrointestinal infections associated with these bacteria. Antibiotic usage can also have an impact on skin and mucosa colonization (such as for methicillin-resistant Staphylococcus aureus) with significantly increased risk of subsequent infections. These forms of ‘collateral damage’ associated with antibiotic use are important considerations when deciding how best to use antibiotics to prevent or treat infections in the hospital (and community) setting. This review looks at some of the ecological effects of antibiotics used in the hospital and their potential for collateral damage of the nosocomial environment. Collateral damage is becoming an increasing problem due to the increasing severity of illness in hospitalized patients and the increasing use of broad-spectrum antibiotics. The ultimate goal is to understand how to better use antibiotics to optimize their beneficial effects, while minimizing risk of collateral damage, in other words, to improve antibiotic stewardship within hospitals and other institutions.

Beyond the target pathogen: ecological effects of the hospital formulary. (2011) Curr Opin Infect Dis. 24 Suppl 1: S21-31
Antibiotic therapy has the potential for intended as well as unintended consequences due to ecological effects that extend beyond the target pathogen. This review examines some of the collateral damage and collateral benefit that may occur when using antibiotic therapy. Antibiotics excreted in the gastrointestinal tract cause alterations of the indigenous flora. Such disruptions may increase the risk of colonization and overgrowth of pathogenic bacteria, including resistant species, with the potential for serious infection for an individual patient as well as possible hospital-wide dissemination resulting in local outbreaks of infection. For example, Clostridium difficile infection (CDI), and particularly associated diarrhea and colitis, is a potentially serious and growing problem in hospitals worldwide, and is associated with disruption of gut flora through use of broad-spectrum antibiotics, especially those with antianaerobic activity. Infection control measures and improved antibiotic stewardship are key measures for CDI prevention. Another example is the risk of intestinal colonization and overgrowth with resistant bacteria, which is heightened in surgical patients requiring antimicrobial therapy for intraabdominal infections. Results from two Optimizing Intra-Abdominal Surgery with Invanz studies (OASIS-I and OASIS-II) suggested emergence of resistant Enterobacteriaceae was less likely in these patients treated with ertapenem than in those treated with ceftriaxone/metronidazole or piperacillin/tazobactam. Finally, recent studies have reported that increased use of a nonpseudomonal carbapenem such as ertapenem does not reduce the susceptibility of Pseudomonas aeruginosa to pseudomonal carbapenems, for example, imipenem or meropenem. In fact, data from one study showed increased ertapenem/decreased imipenem use was associated with improved susceptibility of P. aeruginosa to imipenem, probably due to decreased selective pressure for resistant species. Improper antibiotic use can be associated with detrimental effects related to the ecological impacts of these drugs. Improved antibiotic stewardship and appropriate infection control measures are key to minimization of the collateral damage associated with antibiotic therapy and may even have collateral benefits.

From the outside and within, we are constantly bombarded with a myriad of diverse microbial species. However, our bodies are equipped with an evolutionarily conserved innate immune defense system that allows us to thwart potential pathogens. Antimicrobial peptides (AMPs) are a unique and assorted group of molecules produced by living organisms of all types, considered to be part of the host innate immunity. These peptides demonstrate potent antimicrobial activity and are rapidly mobilized to neutralize a broad range of microbes, including viruses, bacteria, protozoa, and fungi. More significantly, the ability of these natural molecules to kill multidrug-resistant microorganisms has gained them considerable attention and clinical interest. With the growing microbial resistance to conventional antimicrobial agents, the need for unconventional therapeutic options has become urgent. This article provides an overview of AMPs, their biological functions, mechanism of action, and applicability as alternative therapeutic agents.

Presently, AMPs represent one of the most promising future strategies for combating infections and microbial drug resistance. This is evident by the increasing number of studies to which these peptides are subjected. As our need for new antimicrobials becomes more pressing, the question remains: can we develop novel drugs based on the design principles of primitive molecules?

Antimicrobial Peptides: Primeval Molecules or Future Drugs? (2010) PLoS Pathog 6(10): e1001067. doi:10.1371/journal.ppat.1001067

Related:

• Antimicrobial Peptides
• Antimicrobial Peptides: Primeval Molecules or Future Drugs?
• How to avoid getting killed

From the outside and within, we are constantly bombarded with a myriad of diverse microbial species. However, our bodies are equipped with an evolutionarily conserved innate immune defense system that allows us to thwart potential pathogens. Antimicrobial peptides (AMPs) are a unique and assorted group of molecules produced by living organisms of all types, considered to be part of the host innate immunity. These peptides demonstrate potent antimicrobial activity and are rapidly mobilized to neutralize a broad range of microbes, including viruses, bacteria, protozoa, and fungi. More significantly, the ability of these natural molecules to kill multidrug-resistant microorganisms has gained them considerable attention and clinical interest. With the growing microbial resistance to conventional antimicrobial agents, the need for unconventional therapeutic options has become urgent. This article provides an overview of AMPs, their biological functions, mechanism of action, and applicability as alternative therapeutic agents.

Presently, AMPs represent one of the most promising future strategies for combating infections and microbial drug resistance. This is evident by the increasing number of studies to which these peptides are subjected. As our need for new antimicrobials becomes more pressing, the question remains: can we develop novel drugs based on the design principles of primitive molecules?

Antimicrobial Peptides: Primeval Molecules or Future Drugs? (2010) PLoS Pathog 6(10): e1001067. doi:10.1371/journal.ppat.1001067

Related:

• Antimicrobial Peptides
• Frogs vs Bacteria

Marine natural products are a continued focus for drug discovery and have provided many important therapeutic agents. Lead compounds with biomedical potential have been isolated from marine invertebrates, bacteria, and fungi. Each year numerous compounds with an array of biological activities are reported, but to-date only 13 molecules have entered into the clinical pipeline. Four molecules have been approved for clinical use, one of which is approved only in the EU. The approved molecules include two nucleosides based on sponge-derived nucleosides, a cone snail peptide, and a metabolite isolated from a tunicate. Marine microbes have received growing attention as the sources for bioactive metabolites and have great potential to increase the number of marine natural products in clinical trials. The sustainable and economic supply of the active pharmaceutical ingredient is often easier to achieve for compounds produced through microbial fermentation approaches versus the cultivation of slower growing macroorganisms.

Marine natural products provide an excellent opportunity to study diverse and unique compounds not readily accessible from any other source leading to expansion of the pharmaceutical pipeline. Marine microbes can produce unique compounds covering new chemical space, and the utility of marine natural products is expanding beyond its original role in identification of new prototype drug leads into fields of study involving sustainable supplies of unique molecules using biosynthesis in conjunction with synthesis. Perhaps the greatest impact marine natural products has played is in revealing that unexplored and previously inaccessible chemical space can contribute to growth in the pharmaceutical pipeline. Improved methodologies in fermentation technologies, biosynthesis, and synthesis provide opportunities to both create and supply drug leads that would not be available by any single method independently. As a result pharmaceutical biotechnology in the future is certain to provide increasingly sophisticated molecular architecture assembled using biosynthesis and synthesis in concert.

The expanding role of marine microbes in pharmaceutical development. Curr Opin Biotechnol. Oct 16 2010
Marine microbes have received growing attention as sources of bioactive metabolites and offer a unique opportunity to both increase the number of marine natural products in clinical trials as well as expedite their development. This review focuses specifically on those molecules currently in the clinical pipeline that are established or highly likely to be produced by bacteria based on expanding circumstantial evidence. We also include an example of how compounds from harmful algal blooms may yield both tools for measuring environmental change as well as leads for pharmaceutical development. An example of the karlotoxin class of compounds isolated from the dinoflagellate Karlodinium veneficum reveals a significant environmental impact in the form of massive fish kills, but also provides opportunities to construct new molecules for the control of cancer and serum cholesterol assisted by tools associated with rational drug design.

Related:

• Biofilms Use Chemical Weapons
• New Approach for the Discovery of Antibiotics
• Predator and Prey

Polymyxins are the last resort in the therapy of infections caused by extremely multiresistant Gram-negative bacteria. However, their nephrotoxicity may complicate the therapy or even require its discontinuation. Whether new derivatives are less toxic in relevant animal models in vivo than older polymyxins remains to be seen. The future will also show whether resistance to polymyxins will evolve to limit their use. The use of polymyxin compounds in combination with another antibiotic may reduce the risk of resistance developing. We need to be very careful with our remaining drugs of last resort.

Polymyxins and their novel derivatives. Curr Opin Microbiol. Sep 23 2010
The emerging very multiresistant Gram-negative bacteria cause remarkable therapeutic challenges. There are no novel classes of agents in clinical development for the treatment of Gram-negative infections. Polymyxins such as polymyxin B and colistin were abandoned in the seventies but are now back in the therapy as the last resort. Their nephrotoxicity may complicate the therapy or even necessitate its discontinuation. Less toxic polymyxin derivatives would be highly welcome. Novel derivatives lack in strategic positions two of the five cationic charges of polymyxins, differ from polymyxins in their renal handling and affinity to kidney brush-border membrane, and are in preclinical studies. Less characterized other recent derivatives, also reviewed here, have increased the collective knowledge on the structure-function relationships in polymyxins. Acquired resistance to polymyxins has been encountered. However, the resistance mechanism compromises the function of the bacterial outer membrane as a permeability barrier to other noxious agents.

Related:

• Designer drugs for discerning bugs. PNAS USA September 27 2010,. doi: 10.1073/pnas.101254710
• Domagk, Fleming, Waksman and the Third Man
• The Good, the Bad and the Ugly of Antibiotics