Effects of sub‐MIC of β‐lactam antibiotics on biofilms.
Abstract
It is generally accepted that bacteria in biofilm are more resistant to antibacterials than their planktonic counterparts. For numerous antibiotics, it has been shown that minimal inhibitory concentrations (MICs) for bacteria grown in broth are much lower than the minimal biofilm inhibition concentrations. While sub‐inhibitory concentrations, that is, amounts of antibacterials below the MIC, do not either influence or suppress to some extent or other the bacterial growth in liquid media, these same amounts of drugs, natural substances, etc., may have diverse effects on bacterial biofilms, ranging from suppression to stimulation of the sessile growth and varying with regard to the bacterial species and strains. This is a source of additional risks for both biofilm infection of host tissues and contamination indwelling devices. When considering the data for biofilm modulation, differences in experimental protocols should be taken into account, as well as the strain‐specific mechanisms of biofilm formation.
Keywords
- biofilm
- sub‐MIC
- antibiotics
- bacteriocins
- antimicrobial peptides
- plant metabolites
1. Introduction
While the development of antibiotics during the twentieth century resulted in remarkable advances in the fight against infectious microorganisms, it was unfortunately paralleled with the highly increasing risks for the development of antibiotic resistance. These risks are a consequence of the extensive use of antibacterial preparations in both human medicine and agriculture. Resistance has become a threat to human and animal health worldwide, and it necessitates the development of key measures. Among these, the identification of critical points of control, the development of surveillance measures, and the prevention of environmental contamination are in focus [1].
In the aquatic and terrestrial environments, the contaminated sites (wastewater systems, pharmaceutical factories effluents, animal husbandry facilities, etc.) are characterized by the presence of subtherapeutic concentrations of antibiotics [1–3]. Thus, bacteria present in the environment are often subjected to drug amounts lower than the minimal inhibitory concentrations (MICs) [4]. Antimicrobial sub‐MICs are encountered in the human body as well, during treatment, which can occur irregularly at intervals at the site of infection [5] or in cases of low‐dose antibiotic prophylaxis [6]. When microorganisms grow in the presence of sub‐MICs, the antibiotics can potentially alter the physicochemical characteristics of microbial cells, their functions, and the expression of some virulence genes [7]. While sub‐MICs generally do not interfere with bacterial growth dynamics, the microorganisms are subjected to stress. As a way to counter stress, microbes would often form biofilms both in external environments and on indwelling medical devices [3, 8, 9].
It is noteworthy that, when MICs or sub‐MICs are considered, this concerns values obtained with bacteria grown in liquid media, that is, as plankton. Such will be the use of the term also in the present review. In biofilms, the inhibitory doses exceed 10 to even 1000 times these of plankton [1, 9, 10]. Interestingly, when plankton and bacteria dispersed from biofilm have been examined, they were shown to have similar antibiotic susceptibility [11]. Hence, increased resistance is likely associated with characteristics that are a consequence of the structure of the sessile microbial communities. They themselves represent heterologous microenvironments in which gradients of physical and chemical parameters exist [3]. The advantages of these structured bacterial communities comprise limited antibiotic diffusion, enhanced transmission of resistance genes, expression of efflux pumps, drug adsorption by extracellular matrix, as well as the presence of metabolically inactive persister cells [12].
Provided the growing concern about the wide spread and the role of environments containing subinhibitory amounts of antibacterials, the present review will focus on the interplay of sub‐MICs with biofilm growth and/or detachment. In a previous review, the antibiotic‐induced biofilm formation has been discussed [13]. However, the sub‐MIC of antibiotics, but also other antibacterials (e.g. antibacterial peptides, natural and synthetic substances, etc.), dependent on the combination drug‐bacterial strain or species, may have diverse effects on biofilm, from suppression through no effect to promotion. This determined the aim of the present review: to summarize current data and concepts about the modulation of biofilm growth by sub‐MICs of antibacterial substances.
2. Sub‐MIC of antibiotics and biofilms
While it was initially believed that antibiotics in nature have the role for fighting against competitors, and that therefore also sub‐MICs would reduce virulence, recent evidence reveals a more complicated picture, showing the capacity of some antibiotics at low dose to act as chemical signals to modulate metabolic processes [14] or regulate gene (including virulence gene) expression [15].
The idea on the effects of antibiotic sub‐MICs on biofilms is getting more and more complicated with the accumulation of experimental data. This puts forward the question of methodology. The conventional approaches to antibiotic sensitivity do not apply to biofilm‐grown bacteria [9]. Due to the potentially very high intrinsic biofilm resistance, the focus has mainly been put on their prevention [16]. Probably for this reason, most results have been obtained while applying the drug during the sessile growth, with only a few studies testing the agent's effects on pre‐formed biofilms [17–19]. The routinely applied methodology is to test biofilm biomass on 96‐well plates by the crystal violet assay, with only a few other studies that explore cell viability as well, for example, the viable cell counts [20] or live‐dead staining for fluorescence microscopy.
We have summarized the available experimental data on the action of sub‐MICs of antibiotics on biofilms in Table 1–5. We could find no strict pattern with regard to the effects of the separate groups of antibiotics. All groups were shown to influence some biofilms positively, and others, negatively. An important observation is the bacterial species and strain specificity of the response to the sub‐MICs. Thus, sub‐MICs of ampicillin increased biofilm growth of
Antibiotics | Amount | Bacteria/strains | Effect on biofilm | Ref. |
---|---|---|---|---|
Dicloxacillin | 1/2 MIC | 32–60% BF inhibition | [29] | |
8 μg/ml | BF biomass reduction; decreased synthesis of the EPS, poly‐ |
[16] | ||
1/16–1/2 MIC | Dose‐dependent BF suppression | [25] | ||
1/8 MIC | No effect | [26] | ||
Methicillin | 1/3–1/8 MIC | Denser BF formed by the strain and its small‐colony variants | [30] | |
Nafcillin | 0.0625–0.5 MIC |
Increase in 93% of the tested strains, no effect in 7% | [9] | |
1/3–1/8 MIC | No effect on BF | [30] | ||
Cefazolin | 1/2 MIC | 32–55% BF inhibition | [29] | |
0.0625–0.5 MIC |
Increase in 13% of the tested strains, no effect in 80%, and decrease in 7% | [9] | ||
0.5 MIC | BF decrease | [31] | ||
Cefalotin | 1/3–1/8 MIC | Three‐ to fourfold denser BF formed by the strain and its small‐colony variants | [30] | |
Cefoperazone | 1/3–1/8 MIC | No effect on BF | [30] | |
Cefotaxime | 1/2–1/16 MIC | At 1/2 MIC—significantly increased production of BF and EPS | [5] | |
Ampicillin | 0.005–500 μg/ml |
BF reduction | [21] | |
0.1–1.1 μg/ml | Sub‐MIC (0.3–0.7 μg/ml) stimulate BF formation | [6] | ||
1/2–1/1024 MIC |
BF stimulation at MIC, no effect of sub‐MIC |
[6] | ||
10 μg/l | No effect on BF | [22] | ||
Imipenem | 2–4 μg/ml | BF induction, changes in BF morphology, upregulation of |
[32] | |
0.03 and 0.125 μg/ml |
73 isolates |
BF stimulation | [33] | |
Ceftazidime | 1/2–1/8 MIC | 5 clinical isolates strains |
BF inhibition and reduction of viable cell counts | [20] |
0.125–1.0 MIC |
5 strains |
BF inhibition | [24] | |
2; 8; 32 mg/l | 6 clinical isolates of |
Synergistic effect with polymorphonuclears against developed 48 h BF | [34] |
Antibiotics | Amount | Bacteria/strains | Effect on biofilm | Ref. |
---|---|---|---|---|
Ciprofloxacin | 1/16–1/2 MIC | Dose‐dependent BF suppression | [25] | |
1/2–1/16MIC | Inhibition of BF formation and EPS synthesis | [5] | ||
0.1–1.1 μg/ml | BF stimulation by sub‐MIC (0.4–0.9 μg/ml) | [6] | ||
1/2–1/1024 MIC | Statistically significant BF increase and upregulation of BF‐associated genes at 1/4 MIC | [6] | ||
1/2–1/8MIC | 5 clinical isolates |
BF inhibition and reduction of viable cell counts | [20] | |
1/2–1/64 MIC | Dose‐dependent BF inhibition | [23] | ||
0.5 × MIC | Reduction of BF formation and survival of the BF bacteria | [18] | ||
1/2–1/8 MIC | Reduces BF growth and pre‐formed BF | [17] | ||
0.125–1.0 MIC | 5 strains |
BF inhibition | [24] | |
2; 8; 32 mg/l MIC | Synergistic effect with polymorphonuclears against developed 48‐h BF | [32] | ||
0.001–100 mg/l | BF reduction | [15] | ||
Norfloxacin | 1–10,000 mg/l | BF stimulation by 1 mg/l | [8] | |
1–10,000 mg/l | BF stimulation by 1 mg/l | [8] | ||
1/2–1/8 MIC | BF inhibition and reduction of viable cell counts | [20] | ||
1/2–1/64 MIC | Dose‐dependent BF inhibition | [23] | ||
1/2–1/8 MIC | Suppression of BF growth and reduction of pre‐formed BF | [17] | ||
1/16–1/2 MIC | Dose‐dependent biofilm suppression | [25] | ||
Ofloxacin | 1/2–1/8MIC | BF inhibition and reduction of viable cell counts | [20] | |
1/2–1/64 MIC | Dose‐dependent BF inhibition | [23] | ||
0.5 × MIC | No effect on BF formation | [31] | ||
1/2–1/8 MIC | Suppression of BF growth and reduction of pre‐formed BF | [17] | ||
1/2–1/8 MIC | Biofilm inhibition and reduction of viable cell counts | [20] | ||
Levofloxacin | 1/2–1/64 MIC | M89; M65; M100; M74) |
Dose‐dependent BF inhibition | [23] |
0.0625– 0.5 MIC | Increase in 20% of the tested strains, in 47% no effect, and in 40% decrease | [9] | ||
Moxifloxacin | 1 μg/l | 3362‐33; 3362‐34) |
No effect on BF | [22] |
1/2–1/8 MIC | BF inhibition and reduction of viable cell counts | [20] | ||
0.03–0.06 MIC | Decrease in adhesion and BF formation | [7] | ||
2; 10; 50; 100 x MIC | No effect on BF | [35] | ||
1 μg/ml | BF inhibition | [36] | ||
1/2–1/8MIC | BF inhibition and reduction of viable cell counts | [20] | ||
Grepafloxacin | 1/2–1/8MIC | BF inhibition and reduction of viable cell counts | [20] | |
Pefloxacin | 1/2–1/8 MIC | Reduces BF growth and pre‐formed BF | [17] |
Antibiotics | Amount | Bacteria/strains | Effect on biofilm | Ref. |
---|---|---|---|---|
Erythromycin | 1/16–1/2 MIC | Dose‐dependent BF suppression | [25] | |
1/8 MIC | BF increase | [26] | ||
0.25 MIC | BF inhibition in 4 strains; BF enhancement in 20, other strains—unaffected | [27] | ||
Azithromycin | 1/2–1/16 MIC | BF inhibition by 1/4 and 1/2 MIC | [25] | |
2.5–10 mg/ml | BF reduction | [37] | ||
0.125 μg/ml | Decreased BF formation, reduction of established BF | [19] | ||
8 μg/m | BF inhibition | [36] | ||
sub‐MICs | Dose‐dependent BF reduction | [38] | ||
Clarithromycin | 1 μg/ml | BF inhibition | [36] | |
MIC b/n 50–550 mg/ml | Sub‐MIC result in altered structure and architecture of BF | [39] |
Antibiotics | Amount | Bacteria/strains | Effect on biofilm | Ref. |
---|---|---|---|---|
Gentamycin | 1/2–1/16 | Inhibition of BF formation and EPS synthesis | [25] | |
0.1–1.1 μg/ml | Statistically significant BF increase by 0.6—0.7 μg/ml |
[6] | ||
1/2–1/1024 MIC | Statistically significant BF increase by 1/32 MIC |
[6] | ||
8 μg/ml | No effect on BF | [19] | ||
From sub‐MIC up to 100× MIC | BF increase | [11] | ||
0.1–1.5 μg/ml MIC | BF increase | [40] | ||
Streptomycin | 0.5–2 μg/ml | BF increase, induction of BF‐associated genes |
[22] | |
Tobramycin | 0.05–2 μg/ml | BF increase | [40] | |
0.3; 0.5; 1.0 μg/ml | BF reduction | [41] | ||
0.001–100 μg/l | BF reduction | [15] | ||
Amikacin | 0.5× MIC | Reduction of BF formation and survival of the BF‐bacteria |
[18] | |
2; 8; 32 mg/l | Synergistic effect with polymorphonuclears for developed 48‐h BF |
[32] | ||
Kanamycin | 10–110 μg/ml | BF increase | [40] |
Antibiotics | Amount | Bacteria/ strains | Effect on biofilm | Ref. |
---|---|---|---|---|
Streptogramins Quinupristin‐dalfopristin |
0.5 μg/ml | Enhancement of |
[28] | |
0.0625–0.5 MIC | Increase in 20% of the tested strains; in 47% no effect and in 33% decrease | [9] | ||
Glycopeptides Vancomycin |
1/2 MIC | 8–24% BF inhibition | [29] | |
0.0625–0.5 MIC | Increase in 27% of the tested strains; in 47% no effect and in 27% decrease | [9] | ||
0.5× MIC | Decrease in BF | [31] | ||
Tetracyclins Tetracyclin |
0.005–500 μg/ml | Significant BF increase in the presence of (pBR322) | [21] | |
0.0625–0.5 MIC | Increase 7% of tested strains; decrease 93% | [9] | ||
0.5–2 μg/ml | BF increase | [22] | ||
0.01–100 mg/l | BF reduction | [15] | ||
0.5 μg/ml | Enhancement of |
[28] | ||
DHFR inhibitors Trimethroprim‐sulfamethoxazole |
0.0625–0.5 MIC | Increase in 20% of the tested strains, in 40% no effect, and in 40% decrease | [9] | |
1/2–1/8 MIC | 5 clinical isolates strains |
BF inhibition and reduction of viable cell counts | [20] | |
Oxazolidonones Linezolid |
0.0625–0.5 MIC | In 80% no effect, in 20% decrease | [9] |
Antibiotics with identical mechanisms of antibacterial action, for example, gentamicin and erythromycin, may have different effects on biofilm [19, 29]. In addition, the sub‐MICs of a given antibiotic may have diverse effects on different strains of one species of microorganism. For example, such is the case with the effects of cefazolin and levofloxacin on 15 isolates of
Sub‐MICs of antibiotics have the potential to affect the structure of individual bacterial cells. Changes of morphology have been registered in several studies. For instance, sub‐MIC of penicillin induced filamentation of cells of
The extracellular biofilm matrix is an important component of these structured microbial consortia. It has both structural and protective functions. In the interplay with the antibiotics, its barrier role against drug penetration should be underlined [46]. For the time being, available publications show a strict correlation between the effects of sub‐MICs on the biofilm and on the extracellular matrix components. More data are available on the extracellular polysaccharide (EPS). In cases of biofilm biomass reduction (e.g. by gentamicin and ciprofloxacin on
Sub‐MICs of antibiotics can interact with the bacterial‐host interactions. Together with their capacity to affect phenotypes, they can influence bacterial sensitivity to oxidative stress [45], suppress host proinflammatory responses [6], and cooperate with host polymorphonuclear leucocytes to destroy biofilms [34].
There is evidence that in nature, antibiotics at non‐inhibitory concentrations can have the role of signalling molecules that can interfere with quorum sensing [4, 42]. It was shown that sub‐MICs of antibiotics influence quorum‐sensing‐related phenotypes of
Sub‐MICs of antibiotics can interact with bacterial regulation mechanisms and gene expression. Transcriptomic studies indicated that the expression of approximately 5% of bacterial promoters may be affected [13]. Genes related with antibiotic resistance should be mentioned in the first place. There was a correlation between the transcription of the
3. Antibiofilm bacterial metabolites
The capacity of released metabolites of bacterial species and strains to modulate biofilm growth of other bacteria is continuously in focus because of the potential for the isolation of novel biofilm modulating substances. As an initial screening step, the action of cell‐free supernatants (CFSs) is tested. The activities may vary from stimulation [56, 57] to suppression [58, 59]. Noteworthy, the effects of CFSs on bacterial growth in liquid media do not predict the effects on sessile growth. Thus, subinhibitory amounts of 10-2 diluted CFSs from two bacteriocinogenic strains of
Bacteriocins are proteins/peptides produced by prokaryotes which are active against other bacterial species or strains. For example, colicins are produced by some strains of
Mupirocin is an antibacterial substance of the monoxycarbolic acid class that was originally isolated from
4. Antimicrobial peptides and biofilm modulation
The host‐bacterial interactions are also explored with the aim of identifying of novel molecules that would help overcoming the bacterial resistance mechanisms and combating infections. One important group of substances is that of the antibacterial peptides, an important part of the innate immune system.
Colistin is a cationic antimicrobial peptide which is gaining importance in the fight against
The major human host defence peptide LL‐37 is found in mucosal surfaces, the granules of phagocytes, as well as in bodily fluids. At very low concentrations, far below those that kill or inhibit the growth of
The synthetic antimicrobial peptide 1018, derived from the bovine neutrophil defence peptide bactenecin, has recently been identified as biofilm inhibitory compound. While not reflecting on bacterial growth, it could prevent the biofilm growth of
Invertebrate antibacterial responses are also explored. Thus, thanatin is an insect antimicrobial peptide on the basis of which a shorter synthetic derivative, R‐thanatin, was synthesized. When applied in sub‐MIC amounts to
5. Subinhibitory amounts of plant substances
The application of plants for treatment of illness dates back to the very early moments of mankind history, and has laid the basis of modern phytotherapy. The studies on the antibacterial activities of medicinal plant products have a long tradition, more recently expanded to biofilm research. Studies include tests on essential oils and plant extracts, partially purified enriched fractions, as well as isolated pure substances. Also, plant products may be used as a basis for chemical modifications aiming improved antibiofilm activity.
Among the plant products, essential oils are most popular for their wide use in ethnomedicine. Some of them that have antibacterial action proved successful against bacterial biofilms as well. Among the essential oils that at subinhibitory amounts could suppress sessile growth are, for example, these from
Methanol and aqueous branch extracts of five
In a study on 14 fractions from plant extracts, the total extract and the phenyl propanoid‐containing fraction from
Carvacol is an antimicrobial monotherpenic phenol with antibacterial potential that is present in many essential oils. In subinhibitory doses, it suppressed sessile growth of a number of Gram‐positive and Gram‐negative bacteria [80, 81]. Polyphenols from muscadine grapes with antioxidant and antibacterial activity, at 0.5 MIC, inhibited biofilm growth of
Fenchone is a substance that is present in many essential oils. It had neither antibacterial nor antibiofilm effects on a panel of Gram‐positive and Gram‐negative strains. This molecule was used to synthesize its chemical derivatives. While the substitutions did not improve the antibacterial properties against
6. Other compounds with biofilm‐modulating potential
Other substances have also proved a good anti‐biofilm potential when applied in sub‐MICs. For example, sodium ascorbate, together with suppressing
As an opposite effect, the biocides used in food processing facilities, trisodium phosphate, sodium nitrite, and sodium hypochlorite, when applied in sub‐MICs, enhanced the capacity of
7. Some final considerations
Presently, there is growing concern about the relationship between the rise of widespread antibiotic resistance and the role of environments containing subinhibitory amounts of antibacterials [1]. As a major risk for human health, biofilm communities provide the bacteria with prerequisites for rapid resistance development [99]. Among the other more direct risks that biofilms may cause to human health, should be mentioned the possibility for enhanced colonization of indwelling medical devices in the presence of subinhibitory amounts of antibacterial substances, and the contamination of surfaces in medical or food‐processing environments. Depending on the aim of a given antibiofilm strategy, different effects may be in the focus. Disinfection of outer surfaces in hospitals and in food industry requires that the used agents have the capacity to detach established biofilms. On the opposite, if biofilms on indwelling devices are concerned, once established, their detachment is hazardous. It may be accompanied with dissemination of the bacteria to other sites in the human body, and there are risks of sepsis [69]. Therefore, the development of medical materials should be directed to biofilm prevention. However, when the effects of a given substance are estimated, the biology of the biofilm as a whole is better to be addressed, starting from the attachment and establishment of the sessile community, and going as far as its detachment. The methodologies used by the predominant amount of the present‐day studies search for the effects of sub‐MICs by applying the tested agents during biofilm growth. It can be recommended that in the future a more standardized methodology is applied which includes as well tests for dispersion of established biofilms and for microbial vitality. The present review showed several critical points in the effects of sub‐MICs of antibacterial substances as biofilm modulators. Among these, the strain‐ and species‐specific responses of the bacteria in their biofilm development, the expression of virulence factors and quorum sensing should necessarily be taken into account when novel antibacterials are tested.
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