Forum: Science & Society

Microbes and Metabolism

Will biofilm disassembly agents make it to market?

Diego Romero and Roberto Kolter

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA

Update

Nearly 12 years after promising results suggested thatantibiofilm agents might be developed into novel thera-peutics, there are no such products on the market. In ouropinion, the reasons for this have been predominantlyeconomic. Recent developments, however, suggest thatthere could still be emerging opportunities for the devel-opments of such products.

When presented with a surface or an interface and condi-tions propitious for growth, bacteria almost invariably willassemble as groups of cells held together by a self-producedpolymeric matrix. Such groups of cells, referred to asbiofilms, are ubiquitous on our planet and represent acommon metabolism-altering strategy in the microbialworld. Rocks on riverbeds, our bodily skin and everyminute soil particle all teem with microbial life [1,2].Indeed, the top few dozen microns at the surface of all ofthe Earth’s oceans are colonized by a gargantuan gelati-nous biofilm [3]. That biofilms represent the predominantform of bacterial life should come as no surprise becausesurfaces serve as an organizing principle for bacterialgrowth, helping to keep cells from being carried away byuncertain currents. In addition, oftentimes surfaces arenutritious and air–liquid interfaces provide optimal accessto atmospheric oxygen such that aerobes can prosper [2].Of course, surfaces have been present since the origin of lifeand it is clear that as a consequence the play of bacterialevolution has been performed largely on the ecologicalstage of surfaces; most bacteria have evolved intricatemechanisms which allow them to form biofilms [1].

Like all forms of life, biofilms have characteristic lifecycles. Although the details of these life cycles exemplifythe remarkable diversity of the microbial world, there aresome general features characteristics of the life of allbiofilms [4,5]. A few cells, or even a single cell, can arriveat a surface and serve as the early colonizers. These cellsnot only will multiply but will also produce the matrix thatis essential for the integrity of the biofilms [2]. However,biofilms do not last forever and they eventually disassem-ble. Disassembly does not just mean the demise of theexisting biofilm, it also provides the means for survivingcells to leave the sessile life style for a time and achieve thedispersal of at least some members of the population. Thisability of biofilms to disassemble has been the focus ofmuch attention because in many cases biofilms form wherehumans do not want them and we yearn for the ability toeradicate them.

Corresponding author: Kolter, R. (rkolter@hms.harvard.edu)

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In clinical settings the effects of biofilms can be devas-tating. If for whatever reason you need to be admitted to ahospital, chances are high that you will be catheterized. Ifyou happen to be in the United States, your catheter wouldbe one of an estimated 300 million that are used annually[6]. Although the overwhelming majority of catheters thatare used greatly aid in the physician’s ability to treat thepatient, a small percentage of them lead to nosocomial(hospital acquired) infections. These infections can havehigh mortality rates owing to the fact that biofilm-associ-ated bacteria express a still poorly understood phenotypicresistance to many antibiotics [7,8]. In the case of centralvenous catheters, which involve more elaborate proceduresto be put into place and are therefore more complicated toreplace if infected, the infection rate ranges from 1 to 5 per1000 catheter days, depending on the setting [9]. Catheter-related infections are thought to result from the fact thatthe surface of the device is perfectly suited for bacterial andfungal colonization. Interestingly, it has been shown thatall catheters, once inserted, become colonized by microbesthat are originally present on the patient’s skin or on thehub of the catheter [7,10]. Exactly what leads only a smallfraction of catheters to cause an infection is not known butthe chances of infection do increase as the time the catheterremains in place increases. Catheters are, of course, justone of many devices that routinely cause infections in asmall fraction of individuals using them. Heart valves,knee and hip prostheses, surgical pins, etc. all have someprobability of becoming the source of an infection [8]. Thefact is that as modern medicine has made huge advances inhelping patients, the placing of indwelling devices hasbecome routine. And although such indwelling devicesprove largely helpful in patients regaining their health,they always provide new surfaces on which microbes canform biofilms. In addition, many chronic infections – whichby definition are difficult to eradicate – result from biofilmsgrowing on bodily surfaces [10]. Examples of these arediabetic ulcers and lung infections in the lungs of patientswith cystic fibrosis. Biofilm formation can be equally prob-lematic in industrial settings [1]. Virtually every surfacethat comes in contact with fluids becomes fertile ground forbiofilm growth. From water pipes to industrial machineryto air cooling towers, all can be rendered less effective as aconsequence of biofilms.

Clearly, there is an unmet need of controlling biofilms inmany settings. Although this fact was recognized for manyyears, the application of molecular genetics approaches tothe study of biofilms in the late 1990 s led to a largeincrease in the interest among scientists in the development

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of biofilm control strategies. A key finding at that time wasthe discovery, in 1998, of the fact that Pseudomonas aeru-ginosa biofilm formation required cell–cell signaling [11].This led to the general feeling among biofilm investigatorsthat small molecules that would interfere with these signal-ing pathways might prove useful for eradicating undesirablebiofilms. In 1999, the mood was upbeat and the path tobiofilm control was clear, as is made evident in this quotefrom a review of that year:

‘‘Our modern view of biofilm infections leads to therealization that their effective control will require aconcerted effort to develop therapeutic agents thattarget the biofilm phenotype and community signal-ing-based agents that prevent the formation, or pro-mote the detachment, of biofilms. The techniques arenow available to undertake such efforts.’’ [10]

Here we are, 12 years later. What have we accom-plished? Are there any widely used antibiofilm products?As far as we know, no. To date there is no great successstory in this field. Up to now we have limited ourselves todescribing the landscape. Yet this is to be an opinionatedpaper. We were simply setting the stage. Now reader, readon for our opinion. Of course, throughout your reading bemindful of why we might have been asked to give ouropinion. We work in the field and are thus likely tohave strong biases. In the spirit of full disclosure youshould know that indeed we are very interested in seeingantibiofilm agents make it to market (see Disclosurestatement).

We feel that research in the area of biofilm disassemblyhas yielded some very promising results. Aside from theearly discovery of cell–cell signaling involvement in biofilmformation, many discoveries have been made on the pro-cess of biofilm disassembly itself. We do not intend todescribe those here, readers are referred to two excellentrecent reviews that cover this matter thoroughly [5,12].Suffice it to say that we now know that biofilm disassemblyoften involves the induction of enzymes that destroy com-ponents of the matrix and thus liberate the biofilm-associ-ated cells [12]. A recent study that we were involved indemonstrated that the incorporation of specific D-aminoacids into the peptidoglycan led to cells being released fromthe matrix [13]. In addition, synthetic biology has comeinto the picture with the development of recombinantphage that both attack biofilm cells and produce matrix-degrading enzymes [14]. Thus, there is now a significantarmamentarium aimed at biofilm disassembly.

Despite the early enthusiasm and recent successes, whyare there no antibiofilm products on the market yet? Itcertainly is not for lack of trying. Early on, many patentapplications were filed and many start-up companies gotoff the ground searching for antibiofilm agents. Indeed, inacademic and industrial laboratories promising agentswere discovered. Yet, today, many of those start-up com-panies have either failed or they have moved on to otherpursuits. We do not think that the failure to develop aproduct has been as a result of the fact that the antibiofilmapproach is intrinsically flawed. Rather, we feel that thepath to product development is long and expensive and thepotential market is not as lucrative as corporations would

like it to be. Add to that the unfortunate timing of historicalevents. As companies were tooling up a decade ago, themarket downturn of 2001 led to the first flight of interestfrom potential investors. Then, as interest began to growagain in development of these sorts of therapeutics, theworldwide recession that started in 2008 sent most inves-tors into a deep retreat. In many ways, the development ofany specialized antibiofilm agents has paralleled what hashappened to the development of novel antibiotics. Andtherein lies the very heart of the problem. The developmentof these novel agents requires an enormous investmentupfront. Yet, the chances of success are extremely small.Therefore, corporations are only willing to invest in whatthey believe will be potentially huge money makers.

Is there a potential huge money maker in the antibiofilmagent arena? We presented the case of catheters abovebecause it helps to illustrate the situation. At first glance, itdoes seem like a remarkable opportunity – 300 millioncatheters used annually in the United States. A catheterthat would achieve zero infection rates would certainly bewelcome. But even if that were possible, perhaps develop-ing a coating that includes an antibiotic and an antibiofilmagent, how much more would such a catheter cost to be ableto recover the costs of its development? And would thehealthcare system, in its current tight budget, be willing topay that premium to reduce a risk that is currently 1–5infections per 1000 catheter days; especially when most ofthose infections could be controlled by replacing the cathe-ter and treating with antibiotics? We feel that similareconomic arguments are being made by potential investorsfor almost all antibiofilm applications. The costs of devel-opment in relation to the possible profits are probablysending most potential investors away from this area.Thus, we feel that the major reasons for the fact that wehave no antibiofilm agents in the market today are eco-nomic and not necessarily scientific. Although such agentsmight be feasible and perhaps even efficacious, theexpected profits are not seen as large enough by investorsto justify the required investment. Of course, this is a grossoversimplification of what is without a doubt a very com-plex issue where many factors come into play. There clearlyare many hurdles that involve, among others, technicalproblems in reducing laboratory discoveries to practice,clinical practice ‘culture’ and vagueness in the regulatorysteps towards approval. Still, when it is all said and done, itis the expected high cost of overcoming these hurdles,packaged above in the term ‘costs of development’,that could be keeping antibiofilm agents from hitting themarket.

Amid the rather grim view expressed above, we do seeglimmers of hope. Ongoing research in academic laborato-ries has indeed provided evidence that biofilm disassemblycan be accomplished with enzymes, phage and small mole-cules [14,15]. There are signs that some corporate interestsare seeing these as potentially profitable areas to invest in.Importantly, there might be an emerging shift away fromdevelopment of therapeutic applications. We feel it doesmake sense for the translation of these technologies intoproducts to start in non-medical arenas, where the route tomarket might be shorter. Whatever is learned from thoseattempts should prove useful for the eventual development

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of therapeutic applications. Most important of all, we feelthat continued research efforts in academic laboratorieswill in all likelihood yield additional promising avenuesthat might someday be translated into products.

Disclosure statementThe authors note that some of their research on biofilms isfunded by BASF (http://research.initiative.seas.harvard.edu/research.html) as part of the BASF Advanced Re-search Initiative at Harvard and by the Harvard Accelera-tor Fund for Research with Commercial Potential. Inaddition, one of us (R.K.) has in the past consulted fornumerous companies involved in developing antibiofilmstrategies and has recently joined the Scientific AdvisoryBoard of Novophage, Inc.

References1 Hall-Stoodley, L. et al. (2004) Bacterial biofilms: from the natural

environment to infectious diseases. Nat. Rev. Microbiol. 2, 95–1082 Lopez, D. et al. (2010) Biofilms. Cold Spring Harb. Perspect. Biol. 2,

a0003983 Cunliffe, M. and Murrell, J.C. (2009) The sea-surface microlayer is a

gelatinous biofilm. ISME J. 3, 1001–10034 Kolter, R. and Greenberg, E.P. (2006) Microbial sciences: the

superficial life of microbes. Nature 441, 300–302

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5 Karatan, E. and Watnick, P. (2009) Signals, regulatory networks, andmaterials that build and break bacterial biofilms. Microbiol. Mol. Biol.Rev. 73, 310–347

6 Edgeworth, J. (2009) Intravascular catheter infections. J. Hosp. Infect.73, 323–330

7 Raad, I. (1998) Intravascular-catheter-related infections. Lancet 351,893–898

8 Davies, D. (2003) Understanding biofilm resistance to antibacterialagents. Nat. Rev. Drug Discov. 2, 114–122

9 Edwards, J.R. et al. (2009) National Healthcare Safety Network(NHSN) report: data summary for 2006 through 2008, issuedDecember 2009. Am. J. Infect. Control 37, 783–805

10 Costerton, J.W. et al. (1999) Bacterial biofilms: a common cause ofpersistent infections. Science 284, 1318–1322

11 Davies, D.G. et al. (1998) The involvement of cell-to-cell signals in thedevelopment of a bacterial biofilm. Science 280, 295–298

12 Kaplan, J.B. (2010) Biofilm dispersal: mechanisms, clinical implications,and potential therapeutic uses. J. Dent. Res. 89, 205–218

13 Kolodkin-Gal, I. et al. (2010) D-amino acids trigger biofilm disassembly.Science 328, 627–629

14 Donlan, R.M. (2009) Preventing biofilms of clinically relevantorganisms using bacteriophage. Trends Microbiol. 17, 66–72

15 Richards, J.J. and Melander, C. (2009) Controlling bacterial biofilms.Chembiochem 10, 2287–2294

0966-842X/$ – see front matter � 2011 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tim.2011.03.003 Trends in Microbiology, July 2011, Vol. 19, No. 7