Antibiotics' slimy foe

There’s something slimy lurking on hospital surfaces and medical devices, as well as in food-processing plants and even patient tissue. This sinister presence is upending public-health efforts and resulting in nasty infections. It’s called biofilm.

Biofilms are complex surfaces composed of adherent communities of microorganisms. They are held together by polymer matrices comprising polysaccharides, secreted proteins, and extracellular DNA. Biofilms can consist of one type of microbe or a combination of bacteria, protozoa, algae, archaea, filamentous fungi, and yeast, which strongly bond to each other and biotic or abiotic surfaces. 

Biofilms proffer an evolutionary advantage over an unmoored (ie, planktonic) existence, according to the authors of a review article published in Frontiers in Microbiology.

“The formation of biofilm appears to be an age-old survival mechanism that provides microorganisms with better options compared to their planktonic cells, including stronger ability to grow in oligotrophic environments, greater access to nutritional resources, improved survival to biocides, enhanced organism productivity and interactions, as well as greater environmental stability,” the authors wrote. “It can be seen that biofilms provide protection for bacteria and make them more suitable for the external environment under certain conditions.”

The following is an examination of biofilm, with a concentration on antibiotic resistance.

Biofilm formation

The formation of biofilm is a complex process that can be broken down into five phases.

1. During the reversible attachment phase, bacteria non-specifically attach to surfaces.

2. During the irreversible attachment phase, bacteria and surfaces interact via bacterial adhesins including fimbriae and lipopolysaccharide.

3. Resident bacterial cells form extracellular polymeric substances.

4. During the biofilm maturation phase, bacterial cells synthesize and release signaling molecules that detect the presence of each other, thus forming a microcolony, with maturation ensuing.

5. During the dispersal/detachment phase, bacterial cells break away from biofilms and return to a planktonic existence

Under stressful conditions, bacteria seek out spatially isolated niches including microcavities in complex mechanical microenvironments. Ensconced in these complex mechanical microenvironments or cytosolic compartments of the host, bacteria are protected from the adverse effects of the environment and proliferate unfettered. Moreover, the tight packing results in collective behavior that is influenced by biologic responses and mechanical effects.

In an empirical study published in Nature Communications, researchers shed light on the relationship between biofilm formation and mechanical stress.

“Using new controlled methods allowing high-throughput and reproducible biofilm growth, we show that biofilm formation is linked to self-imposed mechanical stress. In growing uropathogenic Escherichia coli colonies, we report that mechanical stress can initially emerge from the physical stress accompanying colony confinement within micro-cavities or hydrogel environments reminiscent of the cytosol of host cells,” they wrote. 

“Biofilm formation can then be enhanced by a nutrient access-modulated feedback loop, in which biofilm matrix deposition can be particularly high in areas of increased mechanical and biological stress, with the deposited matrix further enhancing the stress levels,” they added.

Such feedback regulation in response to environmental stressors leads to the constitution of diverse and adaptive biofilms. 

About 80% of chronic and recurrent microbial infections in humans involve biofilms. Microbial cells are 10 to 1,000 times more antibiotic resistant than their free-floating planktonic counterparts.

Biofilms can form on either abiotic or biotic surfaces. Abiotic surfaces include indwelling medical devices, whereas biotic infections occur on host tissue. Urinary tract infections and septicemia can be caused by biofilms growing on heart valves, catheters, contact lenses, joint prostheses, intrauterine devices, and dental units. Implant removal can lead to resolution of infection, but is costly and problematic for the patient. 

Biofilm infections in host tissue often are chronic, including the lung infections of cystic fibrosis, osteomyelitis, prostatitis, otitis media, rhinosinusitis, endocarditis, wounds, periodontitis, dental caries, and recurrent urinary tract infections.

Planktonic microorganisms resist antibiotics via target site mutations, efflux pumps, lower cell permeability, drug modifying enzymes, and drug-neutralizing proteins. Biofilms, however, resist via separate mechanisms, according to the authors of a review article published in Antibiotic Resistance and Infection Control.

“In biofilm communities,” the authors wrote, “antibiotics resistance appears due to various strategies such as slow or incomplete penetration of the antibiotics into the biofilm, an altered chemical microenvironment within the biofilm and a subpopulation of micro-organisms in a biofilm (a type of cell differentiation like to [sic] spore formation). These mechanisms are the consequences of the multicellular nature of biofilms which leads to the antibiotics resistance of biofilm communities.”

Treatment

Classic antibiotic therapy fails to eradicate bacteria in the center of a biofilm. According to limited research on the topic, antibiotics might work to clear infection only when used early during the course of biofilm formation. At early stages, the bacteria could be less entrenched, thus allowing for deeper antibiotic penetration.

According to the literature cited in the aforementioned review article, various potential treatments for biofilm-associated infections other than antibiotics have been proposed. 

First, small products that are naturally produced by bacterial biofilm communities such as D-amino acids and polyamine norspermidine could disperse mature biofilms and prevent biofilm formation of S. aureus and E. coli.

Second, biofilm degrading enzymes such as DNase I, Dispersin B, and a-amylase could degrade structural components of biofilms and permit penetration of antibiotics into biofilm.

Third, bacteria and actinomycetes produce bioactive agents with antibiofilm properties. These natural compounds could be isolated.

Finally, nanoparticles could be used to fight multidrug resistance and biofilm-based infections.