Bacteriophage-Derived Depolymerases against Bacterial Biofilm

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1		Alicja Węgrzyn	+ 3145 word(s)	3145	2021-02-17 04:46:16	\|
2	format correct	Vivi Li	-2 word(s)	3143	2021-02-23 04:30:26	\|

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics10020175

In addition to specific antibiotic resistance, the formation of bacterial biofilm causes another level of complications in attempts to eradicate pathogenic or harmful bacteria, including difficult penetration of drugs through biofilm structures to bacterial cells, impairment of immunological response of the host, and accumulation of various bioactive compounds (enzymes and others) affecting host physiology and changing local pH values, which further influence various biological functions. In this study, we provide an overview on the formation of bacterial biofilm and its properties, and then we focus on the possible use of phage-derived depolymerases to combat bacterial cells included in this complex structure. On the basis of the study, we conclude that, although these bacteriophage-encoded enzymes may be effective in destroying specific compounds involved in the formation of biofilm, they are rarely sufficient to eradicate all bacterial cells. Nevertheless, a combined therapy, employing depolymerases together with antibiotics and/or other antibacterial agents or factors, may provide an effective approach to treat infections caused by bacteria able to form biofilms.

bacterial biofilm bacteriophages phage-encoded depolymerases combined therapy

1. Introduction

Development of multidrug resistance by bacteria is an extremely serious problem in medicine and veterinary ^[1]. Infections by bacteria resistant to most or even all known antibiotics cause severe diseases, characterized by high morbidity and mortality (summarized in ^[1]^[2]). Therefore, development of novel therapeutic approaches is recognized as one of priorities in the era of the “antibiotic resistance crisis” ^[2].

Contrary to early thoughts on bacterial life, these prokaryotic organisms not only occur in a planktonic form, but can also form higher-order structures, called biofilms ^[3]. As in the case of any other biological processes, one can identify positive and negative aspects of biofilm formation for human life. For example, bacterial biofilms are crucial for effective functions of microbial fuel cells, for efficient production of various products during fermentation, and for biological stages of wastewater treatment ^[4]. However, pathogenic bacteria can form biofilms on surfaces of various materials used in medicine, as well as on surfaces of patients’ tissues ^[5]. Importantly, the formation of biofilm causes further resistance of bacteria to antibiotics, even if the same bacteria are susceptible to them when occurring in a planktonic form. As indicated recently, even plastic litter can be used as a surface for accumulation of pathogenic bacteria in the form of a biofilm and development of multidrug resistance ^[6]. Therefore, finding of effective approaches to combat bacteria included in biofilm is an important issue.

2. Bacteriophage Depolymerases as an Alternative to Antibiotics

Phage depolymerases have gained the interest of the scientific world due to their participation in phage adsorption and digestion of bacterial capsules. According to Pires et al., most of these proteins are encoded in the region of structural genes in a phage genome (i.e., tail fibers and base plates) or next to it ^[7]. These phage-encoded enzymes recognize, bind, and digest the polysaccharide compounds of bacterial cell walls ^[8]. Degradation of these structures allows exposing the phage receptor, which is crucial for efficient phage infection of the host ^[9]. Bearing in mind the mechanism of action of phage depolymerases, we can divide them into two classes, hydrolases and lyases. Both groups are focused on the process of degradation of polysaccharides, including capsular polysaccharides (CPSs), lipopolysaccharides (LPSs), O-polysaccharides, or exopolysaccharides (EPSs), produced in the biofilm ^[10]. Some of them can also degrade polypeptides or lipids ^[11]. Interestingly, phage hydrolases mainly have the activities of sialidases, xylosidases, levanases, rhamnosidases, dextranases, and peptidases. This group of enzymes belongs to the O-glycosyl hydrolases that catalyze the hydrolysis of glycosidic bonds ^[7]^[9]. Moreover, another class of depolymerases is represented by hyaluronate, alginate, and pectin/pectate lyases. Their mechanisms of depolymerization do not include water usage and are based on β-elimination to form a new double bond ^[12].

Since the discovery of activities of phage depolymerases, they have become an alternative to antibiotics, especially in the treatment of multidrug-resistant bacteria. Unlike antibiotics, depolymerases can be specific to the host and allow for the natural bacterial flora to remain untouched ^[13]^[14]. They can not only be engineered to increase their degrading activity, but also used as tools for the detection of bacteria ^[15]. Depolymerases may be used in two alternative forms, (i) as tail-spike proteins (TSP) which have depolymerase domains, being components of virions, or (ii) as free enzymes ^[12]. When whole phages are used, they can multiply in sensitive host cells, producing significantly more virions with TSPs. This option might be beneficial if there are difficulties in supplying materials directly to biofilms, e.g., during treatment of clinical biofilm infections, as phages may allow for more effective delivery of these enzymes to the target place ^[16]. On the other hand, phages can transfer genes coding for toxins and antibiotic resistance proteins between bacterial cells, which causes safety issues ^[17]^[18]^[19]. The development of bacteriophage resistance among bacteria is another problem ^[20]^[21]. In contrast, free depolymerases are genetically stable agents, active in harsh external conditions. Development of resistance to these enzymes is unlikely, which is another advantage of free proteins (obtained biotechnologically as products of recombinant genes) over the use of whole phage particles ^[9]^[22]^[23]. In addition, the diffusion of free enzymes seems to be more rapid and effective than that of virion-associated depolymerases ^[16].

As described above, bacterial biofilms are formed mainly with EPSs ^[24]^[25]. Both CPS and EPS layers present large diversity in their polysaccharide content. Differences can be observed at the species and strain levels. In addition, the EPS matrix may present structural heterogeneity across individual biofilms as the physiological state of the host cells, their growth phase, their co-aggregation, and the environmental conditions also affect its composition ^[26]. Therefore, in some cases, a depolymerase that is able to degrade the CPS layer of a particular bacterial strain may not be capable of digesting its EPS layer. In response to the existing tremendous variation in bacterial polysaccharides, huge diversity in phage-derived depolymerases is observed. They present high specificity to a narrow range of target polysaccharides ^[9]. This feature greatly limits polysaccharides that can be digested by a particular depolymerase. In effect, a depolymerase originated from a particular phage may not recognize the cell-surface polysaccharide compounds of closely related bacteria or even those produced by bacteria of the same strain but growing under different conditions ^[16].

Furthermore, susceptibility of biofilms to phage depolymerases is dependent on the content of microorganisms and whether the biofilm is single- or multispecies. Importantly, polymicrobial systems not only are limited to different bacterial species, but may also encompass different genera and even other organisms, such as fungi. In comparison with single-species biofilms, the mixed communities are undoubtedly the dominant form in nature; however, they are more difficult to remove by phage depolymerases ^[27]. Furthermore, as reported by Burmolle et al., bacteria in multispecies biofilms display higher resistance to other antibacterial agents than biofilms formed by these bacterial species alone ^[28]. One possible reason for this is the limitation of antibiofilm agent migration by the presence of a large diversity of EPSs produced by heterogeneously distributed bacteria. In such a heterogeneous community, the action of depolymerases is limited due to the fact that they are highly specific for the host-derived polysaccharides ^[29]. Complex EPSs of multispecies biofilms may not only hinder the penetration of the biofilm by depolymerase-producing phages, but also entrap the phage in the biofilm matrix ^[30], reduce multiplication of the phage due to the presence of phage non-susceptible or metabolically inactive cells ^[31], reduce the presentation of the phage receptor ^[32], or deter the phage depolymerase activity ^[33]. In effect, pockets of unattainable phage-susceptible bacteria are formed, enhancing the structural heterogeneity of multispecies biofilms ^[29].

Importantly, there have been attempts to overcome the abovementioned difficulties in combating polymicrobial biofilm communities. One of them involves phage depolymerases, able to degrade EPSs of different bacterial species. As reported by Skillman et al., over a 90% reduction in dual-species biofilm was obtained using polysaccharide depolymerase, isolated from a bacteriophage ^[34]. On the other hand, multispecies biofilms can also be treated with cocktails consisting of different phages/depolymerases acting on different receptors/structures, and this strategy is even recommended ^[35]^[36] (for more examples, see review ^[29]). In addition, genetic modifications of phages could allow them to produce several depolymerases and extend their host range ^[9]^[26]. They have been subjected to genetic engineering and purified ^[26]. Importantly, free recombinant enzymes are more easily produced than virion-associated depolymerases. Moreover, such recombinant enzymes may be applied at high concentrations, which overcome enzyme production by phages alone. Currently, work is underway to expand the spectrum of their activities ^[37]. In the fight against biofilms (including multispecies communities), depolymerases can also be used in combination therapy with antibiotics, phages, or other agents. Examples of such combination strategies are discussed in Section 4.

The Antibiofilm Activity of Phage Depolymerases: Examples of Applications of Phage Depolymerases against Bacterial Biofilms

EPSs are mainly responsible for the structural and functional integrity of bacterial biofilms and have an influence on their virulence ^[38]. Interestingly, Gutiérrez et al. ^[39] applied the EPS depolymerase Dpo7, derived from bacteriophage vB_SepiS-phiIPLA7, against staphylococcal biofilms. This study revealed that Dpo7 is able to degrade the EPS biofilm matrix of staphylococcal strains from 31% in S. epidermidis ASLD1 to 75% in S. epidermidis LO5081, relative to the control variants. Additionally, the pre-treatment of polystyrene surfaces with Dpo7 resulted in the reduction of biofilm activity and its biomass from 53% to 85% in the majority (67%) of tested strains (the obtained results were dose-dependent and time-independent). In summary, EPS depolymerase Dpo7 may inhibit biofilm formation and can also disperse biofilms generated by different strains of S. epidermidis and S. aureus ^[39].

Moreover, Hernandez-Morales et al. ^[40] isolated a novel bacteriophage Petty that possesses the gene of depolymerase Dpo1 (capable of degrading EPSs) and can infect A. nosocomialis and A. baumannii. The main purpose of that study was to determine the ability of Dpo1 to depolymerize EPSs and to remove bacterial biofilm formed by Acinetobacter strains. In vitro analyses showed that Dpo1 was able to reduce EPS viscosity and to remove biofilms of some of the tested Acinetobacter strains. However, the antibiofilm effect of Dpo1 was not spectacular, and it led to a 20% reduction of the bacterial biofilm. The obtained results may suggest that the phage depolymerase Dpo1 cannot completely destroy bacterial biofilms. On the other hand, Dpo1 may probably decrease the virulence of the tested bacterial strains via the degradation of EPSs ^[40].

In another research, Mi et al. ^[41] investigated the efficacy of newly isolated phage IME180 against biofilms formed by P. aeruginosa. This lytic phage possesses a gene that encodes a functionally active depolymerase. Surprisingly, this phage-derived enzyme is able not only to inhibit the formation of host bacterial biofilms, but also to reduce the biomass of a preformed biofilm. However, complete inhibition of biofilm formation or its removal was not observed ^[41].

It is worth mentioning that the ability to form biofilm is also observed in the group of E. coli bacteria ^[42]. Guo et al. ^[43] isolated and characterized phage vB_EcoM_ECOO78 that infects clinical isolates of E. coli. This phage belongs to the Myoviridae family, and it encodes a functionally active depolymerase Dpo42. Researchers have demonstrated that Dpo42 may degrade the capsular polysaccharides surrounding E. coli cells. Moreover, this enzyme can also exhibit antibiofilm activity in a dose-dependent manner. The highest level of antibiofilm activity was observed when Dpo42 was added to a final concentration of 25 μg/well. However, it was also shown that the depolymerase Dpo42 can significantly prevent biofilm formation, but cannot remove it totally ^[43].

In subsequent studies, depolymerase Dep6 (O91-specific polysaccharide depolymerase) was identified in the lytic T7-like phage, named PHB19, specific for Shiga toxin-producing E. coli (STEC). Dep6 was tested for antibiofilm and antibacterial activities against E. coli strains. Application of the Dep6 enzyme significantly reduced the absorbance of the total 24 h old and 48 h old biofilm biomasses, compared to untreated controls. However, Dep6 did not decrease the number of counted viable bacterial cells. Interestingly, this depolymerase may probably degrade EPS on the surface of the STEC HB10 strain, thus enhancing the susceptibility of this strain to serum killing ^[44].

K. pneumoniae has also demonstrated resistance to a wide range of antibiotics. This pathogen also belongs to the group of bacteria that are able to form biofilms ^[45]. Interestingly, depolymerase Dep42 was identified in lytic bacteriophage SH-KP152226 that represents the Podoviridae family and can lead to the lysis of K. pneumoniae capsular type K47 ^[46]. Treatment with 10 μg/mL Dep42 resulted in a reduction in bacterial counts in the biofilm, compared to the control. Wu et al. ^[46] also demonstrated that EPSs from K. pneumoniae strain 2226 can be degraded by Dep42. These results showed that depolymerase Dep42 weakly reduced the number of colonies in the biofilm but had the ability to degrade the extracellular material of the biofilm, releasing the attached cells. Therefore, it was supposed that that the combination therapy of Dep42 and antimicrobial agents may be considered to eliminate dispersed bacterial cells ^[46].

The examples discussed above concern the activities of phage-derived depolymerases on biofilms under in vitro conditions, in static environments. Such conditions are devoid of human plasma proteins, and they lack in vivo stressors and the response of the immune system. Moreover, in most cases, the experiments did not refer to planktonic infections which usually overlay clinical biofilm infections. Whenever possible, these factors should be included in research as they may have an important role in biofilm eradication and/or prevention.

3. Combination Therapy of Phage-Derived Depolymerases and Different Therapeutic Agents

3.1. Various Antibiotics

The combination therapy is mainly based on the use of depolymerases together with antibiotics. The synergistic action of free or phage-encoded depolymerases with antibiotics gave optimistic results. The phage-encoded depolymerases not only induced susceptibility of bacteria to antibacterial agents, but also were able to penetrate the biofilm and damage its structure, which is usually not achieved when antibiotics are used alone. The undoubted advantage of this therapy is that phage depolymerases allow degrading EPS/CPS/LPS layers, as well as loosen up and peel off the biofilm structure, thereby allowing antibiotics to easily reach the bacteria and expand more effectively ^[7]^[11]^[25]. As an example, the depolymerase produced by lytic bacteriophage KPO1K2 was used with ciprofloxacin. These studies showed that the combined treatment of depolymerase of phage KPO1K2 and the antibiotic worked more effectively against old biofilms than either of agents used alone ^[41]^[42]. In turn, Bansal et al. ^[47] tested the combinations of phage KPO1K2 or bacterial depolymerase with gentamicin against biofilms formed by K. pneumonia strain B5055. In the case of the combined therapy of phage-derived depolymerase and gentamicin, a reduction in bacterial cell number was significant relative to the control variant. Interestingly, this effect was not so spectacular when only gentamicin was used. Moreover, the combination of depolymerase Dep42 with polymyxin was also an effective approach in the fight against bacterial biofilm ^[46].

3.2. Bacteriophages

As both CPSs and EPSs can reduce the efficacy of phage adsorption rate to the surfaces of bacterial cells, the application of whole phage particles, in addition to depolymerases, can increase the phage penetration and expansion within biofilm, thus making it easier for phages to reach the receptors of cells belonging to deeper layers ^[16]^[48]^[49]. Interestingly, phages were also shown to diffuse through alginate exopolysaccharides and cause a reduction in cell number in quite old (20 days) biofilms of P. aeruginosa ^[50]. Another example of such combined therapy is based on the in vitro application of four different agents: (1) lytic phage KP34 with its virion-associated depolymerase KP34p57, (2) the recombinant depolymerase KP34p57, (3) depolymerase-nonbearing lytic phage KP15, and (4) ciprofloxacin against a multidrug-resistant K. pneumoniae 77 biofilm ^[51]. Interestingly, the recombinant depolymerase KP34p57 did not significantly eradicate the biofilm of K. pneumoniae 77. However, its effectiveness increased significantly in the presence of the KP15 phage, which indicates that phage-derived proteins with enzymatic activity may be a promising support to depolymerase-nonproducing bacterial viruses. It was also demonstrated that depolymerase KP34p57 did not improve ciprofloxacin activity, giving similar results to antibiotic action itself ^[51].

3.3. Chemical Compounds

Tait et al. ^[52] tested the effects of treatments of disinfectants and phage enzyme to control Enterobacter agglomerans biofilm formation. Polysaccharide depolymerase from bacteriophage φEnt was used with a disinfectant (a nonionic disinfectant, an amphoteric-based disinfectant, or a quaternary ammonium compound). The obtained results showed that the combination of phage φEnt-derived enzyme and a disinfectant was more effective than either of these used alone. Interestingly, the highest efficacy was observed in the combination of phage enzyme with a nonionic disinfectant ^[52]^[53].

Another interesting research demonstrated that phage-derived depolymerase could destroy about 80% of bacterial cells from Klebsiella biofilm ^[54]. However, Chai and co-workers also noticed that approximately 92% of the bacterial biofilm was eliminated after pretreatment with this virus enzyme followed by chloride dioxide (ClO₂) incubation for 30 min. Interestingly, ClO₂ treatment was less efficient than combination therapy and led to the elimination of only 75% of the Klebsiella biofilm ^[54].

Chhibber et al. ^[55] tested the activity of a phage enzyme in combination with cobalt sulfate (CoSO₄) against biofilm formation by K. pneumoniae strain B5055. According to observations by Hancock et al. ^[56], addition of Zn (II) or Co (II) to the substrate (bacterial cells in growth medium) could lead to inhibition of the growth of E. coli biofilm. Therefore, in these studies, biofilms were grown in minimal media supplemented with 10 μM FeCl₃ and CoSO₄. The results showed that the combination therapy of depolymerase of bacteriophage KPO1K2 and CoSO₄ completely destroyed the young biofilm (up to 2 days old). This was probably possible due to degradation of the EPS matrix, encompassing the biofilm structure, by the depolymerase of the tested virus that facilitated the diffusion of cobalt ions ^[55]. Importantly, such satisfactory results were not obtained with the application of depolymerase-nonproducing phage alone, as well as in combination with CoSO₄ ^[57].

3.4. Natural Compounds

Naturally occurring compounds play essential roles in combination therapy. Chhibber et al. ^[57] studied the efficacy of phages KPO1K2 (K. pneumoniae B5055-specific depolymerase-producing phage), NDP (K. pneumoniae B5055-specific depolymerase-nonproducing phage), and Pa29 (P. aeruginosa PAO-specific depolymerase-nonproducing phage), in combination with xylitol, in the treatment of P. aeruginosa and K. pneumonia biofilms. Interestingly, the most efficient reduction of the mixed-species biofilm was observed when the combined therapies of phage KPO1K2, Pa29, and xylitol or phage KPO1K2 and xylitol was used. This can be explained by the depolymerase-producing ability of KPO1K2. It is suggested that the capsular depolymerase of KPO1K2 virus may hydrolyze the polysaccharide layer formed by K. pneumoniae on the top of the biofilm structure. Therefore, phage KPO1K2 can interact with the bacterial receptor located on K. pneumoniae, thereby causing its lysis. This probably facilitated the penetration of Pa29 and xylitol, leading to disruption of the basal Pseudomonas layer ^[55]. It is worth mentioning that Oliveira et al. ^[58] demonstrated the synergistic effect of honey and phage EC3a (possessing depolymerase activity) against E. coli biofilms. Moreover, they noticed that the effectiveness of this combined therapy is strictly dependent on the type and concentration of honey. Interestingly, the combination of phage EC3a and honey (PF2_25%) revealed more efficient antibiofilm activity than honey or phage alone. Importantly, the combined strategy of phage and PF2_25% prevented the appearance of phage-insensitive mutants ^[58].

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Alicja Węgrzyn

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