title: The physiology and collective recalcitrance of microbial biofilm communities.
abstract: Microbial biofilms impinge upon all aspects of our lives. Whilst much of this impact is positive, there are many areas in which the presence and activities of biofilms are regarded as problematic and in need of control. It is in this respect that biofilms reveal their recalcitrance towards many of the long-established antibiotics, and industrial and medical treatment strategies. The nature of the resistance of biofilms, in spite of much research, remains an enigma. Whilst it is recognized that reaction--diffusion limitation properties of the biofilm matrix towards the majority of treatment agents will impede access, this cannot be the sole explanation of the observed resistance. Rather, it will delay the death of cells within the community to various extents. Similarly, it is recognized that biofilm communities are phenotypically heterogeneous and that their eradication will reflect the susceptibility of the most resistant phenotype. The nutrient and gaseous gradients that generate this heterogeneity will, however, be destroyed as a result of antimicrobial treatments and cause the phenotype of the survivors to alter from slow-growing resistant cells to fast-growing susceptible ones. Accordingly both explanations can only delay death of the community. In order to explain more fully the long-term recalcitrance of biofilms towards such a wide variety of biocidal agents, more radical hypotheses must be considered. Amongst these are that multidrug efflux pumps could be up-regulated on expression of a biofilm phenotype. Whilst this is an appealing and simple explanation, because of its ability to explain the breadth of agents to which biofilms are resistant, recent work has suggested that this is not the case. Alternative hypotheses attempt to explain the diversity of agents by invoking a common cause of death for which singular resistance mechanisms could be applied. It is therefore suggested that an altruistic majority of sublethally damaged cells in a population commit suicide (apoptosis), thereby providing some protection to the survivors. A proportion of cells (persisters) is suggested to be defective, or repressed, in their suicide response, and survive. The persisters thereby benefit from the self-sacrifice of their compatriots and maintain the gene pool. A second explanation of the presence of persisters is that the general stress response, well known to include the adoption of a viable, nonculturable state of quiescence, is up-regulated in small pockets of the biofilm community, where nutrients are particularly scarce. Such quiescent cells noted for their resistance towards the metabolically acting biocides would potentially have their dormancy broken after treatment by the replenished supply of nutrients caused by the death of the majority. A more recent hypothesis suggests that extracellular signals, 'alarmones', released from killed cells might prime recipients into a state of resistance. Thus, in biofilm communities deep lying cells might be alerted into a resistant state by the premature death of peripheral cells. It is equally possible that 'alarmones', in this context, are merely the post-treatment 'wake-up' call to a previously quiescent subset of cells. In this review, we attempt to provide a holistic view of the potential mechanisms by which biofilms express resistance. Since these mechanisms are multifaceted then their impact upon resistance will be considered against the context of biofilm formation, growth and maturation.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Coupland III Building, Coupland Street, University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Gilbert
authors.forename: Tomas
authors.initials: T
authors.lastname: Maira-Litran
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McBain
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Rickard
authors.forename: Fraser W
authors.initials: FW
authors.lastname: Whyte
mesh_terms: D001419:Bacteria / Q000378:metabolism*; D001422:Bacterial Adhesion / Q000502:physiology; D018441:Biofilms / Q000254:growth & development*; D004352:Drug Resistance, Microbial / Q000502:physiology; D019276:Glycocalyx / Q000378:metabolism