Therapies for resistant bacteria

 

Bacteria have the frightening habit of evolving to develop their own immunity or resistance to currently available antibiotics. If this fact is not scary enough, there are several bacteria that have very recently acquired new resistance traits and some of these remain untreatable by any antibiotic drug on the market.  Making matters worse, there is little new research in the development of new classes of antibacterial drugs, mainly due to high costs for research, poor financial returns, and burdensome regulations. With an estimated 80% decrease in the development of new antibiotics since in the 1980’s, there is an acute medical need to prime the fragile pipeline of antibiotics discovery to generate innovative approaches and ultimately new drugs to treat these otherwise untreatable and life-threatening infections.   Read More

Disarming pathogens from their ability to cause infection: antivirulence versus antibiotic drugs

Humans are born without any microorganisms (which include bacteria) on our body surfaces – we are sterile from the perspective of microorganisms. Over the first few days and weeks of birth, our bodies become colonized by microorganisms and ultimately, we end up with more microbial cells than we have human cells on all of our body surfaces.  Nearly all of these microorganisms live within and upon us in symbiosis, help us fight infections, and even some of the microorganisms produce vitamins and other nutrients that are vital to our existence.

Traditional antibiotics work by either killing the bacteria’s cells or preventing cell division and proliferation – by well-known mechanisms without regard to whether the microorganism is “friendly” (beneficial bacteria or microflora) or potentially pathologic to our existence. When so many friendly microorganisms are eliminated, the potentially harmful microorganisms can gain the advantage to multiply and establish themselves in a new environment where there is less competition for nutrients between the friendly and harmful microorganisms. Moreover, these potentially harmful organisms tend to grow resistant to the antibiotic used thus creating antibiotic-resistant strains of microorganisms in their place.  In terms of bacteria, “virulence” and “virulence factors” describe the multifaceted characteristics of bacterial pathogens (microbes) to cause disease in a host (human, animal, insect).

Bacterial antivirulence strategies do not kill pathogens or prevent them from proliferating, but rather disarm pathogens from their ability to create the many harmful products that promote infection.  Targeting the virulence machinery of the microorganism itself, antivirulence drug treatment takes advantage of the key steps in the production of these harmful products by neutralizing one or more virulence factors that a pathogen must use to create an infection. Using relevant models of infection, MGH researchers have shown that by inhibiting or preventing the bacteria from producing their harmful products, the bacteria were no longer harmful. This antivirulence and non-killing approach should preserve the beneficial flora and potentially decrease the development of antibiotic resistance because the approach does not apply any of nature’s pressures of bacterial competition.

Bridging the basic and clinical sciences to address the antibiotic resistance epidemic

Bacterial pathogens can rapidly overwhelm innate defense mechanisms and antibiotic resistance can severely limit therapeutic options for sick patients. In a mission to develop alternative and innovative ways to combat antibiotic resistance, Massachusetts General Hospital (MGH) investigators have developed the first pipeline to permit the identification of patients with a high risk of developing multiple infections following severe injury can be predicted days before infection occurs. This information will ultimately permit personalized therapy, and facilitate the determination of targeted treatment courses, particularly in regard to antibiotic use.  This novel research begins to bridge the new knowledge gleaned from the basic sciences and the world of clinical medicine to open new avenues for the development and testing of innovative therapeutics for severe and untreatable infections.

Virulence-targeted approaches to combat clinical infections

Development of novel, virulence-targeted approaches aimed at drug-resistant bacterial infections has been more than a decade in discovery and supported by multiple organizations including the National Institute of Allergy and Infectious Diseases (NIAID), the Cystic Fibrosis Foundation, and the Department of Defense (DOD).

Researchers through this support have been working to identify promising targets for the development of specific antivirulence drugs to fight Pseudomonas aeruginosa (PA) infection, a leading cause of hospital-acquired infection lethal in almost 50% of patients.  The discovery research focuses on the molecular mechanisms of two major physiological activities – bacterial virulence and persistence.  Persistence is the capacity for a few bacterial cells to adopt a state of tolerance to antibiotic killing.  These few cells provide a reservoir for re-initiation of infection that is ultimately responsible for persistent, chronic, and relapsing infection.

Infected flies with genetic predisposition to cancer develop intestinal cancer

MGH investigators are studying the secretion of bacteria’s small chemical signal molecules that when excreted act to synchronize all bacterial cells in the surrounding environment to produce their many virulence functions in concert (quorum sensing).  Bacteria through this coordinated regulation activate many virulence functions and produce and release chemicals – some of which are toxic, promote antibiotic tolerance, and bacterial persistence.  The investigators have demonstrated that secreted toxic products like pyocyanin from the bacterial pathogen PA negatively interfere with the intestine’s normal self-renewal in the gut of the fruit fly Drosophilia melanogaster in a way that can lead to chronic gastrointestinal diseases.  More importantly, investigators have discovered that PA-infected flies having a genetic predisposition to cancer can go on to develop intestinal cancer.

Biofilm formation by PA over 24 hours makes antibiotic penetration impossible

Some of these released chemicals also promote bacterial biofilm formation, which is the behavior of a group of bacteria to stick to each other on virtually any living or non-living surfaces – in nature and settings like hospitals.  Shown here is a biofilm-forming strain of PA formed on a plastic surface over the course of 24 hours.  You can see that massive aggregates of bacterial cells would make the penetration of antibiotics through the biofilm nearly impossible.  Patients at highest risk of harboring biofilms are those with an open wound, chronic infection, or indwelling medical device like a catheter or implant.

Spero Therapeutics, LLC

MGH investigators are taking innovative approaches to addressing the antibiotic resistance public health crisis.  This antivirulence strategy has been tested for its relevance to human infections and its robustness to be reproducible among various bacterial strains and potentially different microbial species.  From this discovery research, Spero Therapeutics, LLC has been organized to identify and develop first-in-class antiinfectives for severe, drug-resistant infections by targeting these two critical bacterial processes of virulence and persistence.  As a new company, Spero Therapeutics has been supported by Atlas Venture, Partners Innovation Fund, SR One (the VC arm of GlaxoSmithKline), and most recently by Roche.  Spero Therapeutics has been named by FierceBiotech as one of 2014’s Fierce 15 biotechnology companies.

Relevant publications

Rahme LG, Stevens EJ, Wolfort SF, Shao J, Tompkins RG, Ausubel FM.  Common virulence factors for bacterial pathogenicity in plants and animals.  Science. 1995 Jun 30;268(5219):1899-902.  PubMed PMID: 7604262

Rahme LG, Tan M-W, Le L, Wong SM, Tompkins RG, Calderwood SB, et al.  Use of model plant hosts to identify Pseudomonas aeruginosa virulence factors.  Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13245-50. PubMed PMID: 9371831

Lesic B, Lépine F, Déziel E, Zhang J, Zhang Q, Padfield K, et al. Inhibitors of bacterial pathogen intercellular signals as selective anti-infective compounds. PLoS Pathog. 2007 Sep 14;3(9):1229-39. PubMed PMID: 17941706; PubMed Central PMCID: PMC2323289

Apidianakis Y, Pitsouli C, Perrimon N, Rahme LG. Synergy between Bacterial Infection and Genetic Predisposition in Intestinal Dysplasia. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20883-8. PubMed PMID: 19934041; PubMed Central PMCID: PMC2791635

Kesarwani M, Hazan R, He J, Que YA, Apidianakis Y, Lesic B, et al. A quorum sensing regulated small volatile molecule reduces acute virulence and promotes chronic infection phenotypes. PLoS Pathog. 2011 Aug;7(8):e1002192. PubMed PMID: 21829370; PubMed Central PMCID: PMC3150319

Bangi E, Pitsouli C, Rahme LG, Cagan R, Apidianakis Y. Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells. EMBO Rep. 2012 Jun 1;13(6):569-76.  PubMed PMID: 22498775;  PubMed Central PMCID: PMC3367237

Bandyopadhaya A, Kesarwani M, Que Y-A, He J, Padfield K, Tompkins R,  et al.  The quorum sensing volatile molecule 2-amino acetophenon modulates host immune responses in a manner that promotes life with unwanted guests. PLoS Pathogens. 2012 Nov;8(11):e1003024. PubMed PMID: 23166496; PubMed Central PMCID: PMC3499575

Yan S, Tsurumi A, Que YA, Ryan CM, Bandyopadhaya A, Morgan AA, et al.  Prediction of multiple infections after severe burn trauma: a prospective cohort study.   Ann Surg. 2014 Jun 19. Epub ahead of print.  PubMed PMID:24950278; PubMed Central PMCID: PMC4284150

Starkey M, Lepine F, Maura D, Bandyopadhaya A, Lesic B, He J, et al. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. PLoS Pathog. 2014 Aug 21;10(8):e1004321.  PubMed PMID: 25144274; PubMed Central PMCID: PMC4140854

Contact

Laurence (Lory) Rahme, Ph.D.
rahme@molbio.mgh.harvard.edu
617-724-5003

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Grace McDonald-SmithTherapies for resistant bacteria