Biomedical Implications of the Porosity of Microbial Biofilms - Porous Media: Applications in Biological Systems and Biotechnology - page 136

biofilms. Therefore, this locus is a potential candidate for horizontal gene
transfer within the biofilm resulting in an increased antimicrobial resis-
tance.
Quorum-sensing signaling systems synchronize target gene expression and
coordinate biological activity within biofilms (Dong and Zhang 2005). As an
example, N -acylhomoserine lactones are secreted by P. aeruginosa within the
deep regions of the biofilm. These quorum sensors interact with transcrip-
tional activators to direct expression of several factors that facilitate bacterial
persistence, for example, enabling P. aeruginosa to overcome the effects of
antimicrobial agents (Prince 2002).
Adaptation to survival in the biofilm state requires changes in metabolic
and catabolic pathways that can alter the intrinsic activity of antimicrobial
agents in view of their mode of action (Fux et al. 2005). For example, exper-
imental biofilms formed by coagulase negative Staphylococcus (CoNS) are
highly resistant to antibiotics that target cell wall biosynthesis while remaining
susceptible to antibiotics that target ribonucleic acid (RNA) and protein syn-
thesis (Cerca et al. 2005). This response is consistent with a diminished role for
cell wall biosynthesis in the biofilm population and reflects an ongoing role for
transcription and translation in biofilm establishment, maturation, and prop-
agation. It is interesting that so-called small colony variants (SCVs) of bacte-
ria, characterized by a reduced in vitro growth rate due to genotypic changes
in metabolic pathways (Proctor et al. 2006), have been isolated from both
experimental biofilms and patients with biofilm-associated persistent infec-
tions. These include P. aeruginosa SCVs isolated from biofilms grown in vitro
and from cystic fibrosis patients (von Gotz et al. 2004), an E. coli SCV iso-
lated from a chronic prosthetic hip infection (Roggenkamp et al. 1998), and
S. aureus SCVs isolated from patients with cystic fibrosis, osteomyelitis, and
device-related infections (Chatterjee et al. 2007). Genotypic adaptations that
alter metabolic capacity and decrease growth rate may therefore contribute
to antibiotic resistance of some biofilm-related infections.
As most antimicrobial agents target rapidly growing cells, growth rate may
play an important role in mediating biofilm-associated antimicrobial resis-
tance. Deep within the biofilm, a small fraction of bacteria may differenti-
ate into a protected phenotypic state, that is, slow or nongrowing bacteria
(Lewis 2001). These cells have been referred to as “persisters” and may be
present in relatively high numbers in the deeper section of a given biofilm.
Antimicrobial treatment of bacterial biofilms may lead to eradication of most
of the susceptible population while the small fraction of persister cell vari-
ants may survive and affect biofilm reconstitution following discontinuation of
antimicrobial therapy. This, however, may depend on the specific antimicrobial
agent. Penicillin, for example, does not kill nongrowing cells. Some of the newer
β -lactam agents, for example, cephalosporins, carbapenems, aminoglycosides,

and fluoroquinolones can kill nongrowing bacteria, although they are more
effective at killing growing cells (Brooun et al. 2000).