**3. Approaches aimed at overcoming biofilm resistance**

Biofilm infections can be treated and dispersed by the mixture of traditional antibiotics and substances called biofilm disrupting. The dissolution of biofilm is the first step in the ability of the host organism's immune system to remove microbial pathogens [55]. The combined antibiotics with the biofilm-dispersing medicines can bring a promising outcome. Most biofilm-dispersing medicines do not kill the pathogenic cells when they are used alone. For instance, patulin was analyzed with the aim of acyl-homoserine lactone removal in *P. aeruginosa*, but it had no effect on the existence of *P. aeruginosa* cells in a given biofilm. Although only patulin had no effect on the *P. aeruginosa,* the combination of patulin with antibiotic tobramycin was more effective and caused serious killing of the bacterial cells [56]. Another study showed that the mixture of the quorum controlling compounds with the antibiotic tigecycline increased the susceptibility of *S. aureus* fourfold compared to tigecycline alone [57]. Furthermore, the treatment of *S. aureus* with the mixture of cis-2-decenoic acid and ciprofloxacin is improved from 11 to 87% compared to antibiotic alone.

Considering the rising number of antibiotic-resistant pathogens, QS inhibitors can be used as a mixture with the remaining sensitive antibiotics to complement their effects. These molecules mainly act by suppressing the QS system, and their practice with antibiotics leads to effective cure at much lower dosages of the drug than necessary, which may result in reduced therapeutic costs. These combinations can be beneficial in the cure of chronic infections, such as chronic urinary tract, cystic fibrosis, or prosthetic infections and biofilms are a barrier to antibiotic diffusion in these chronic diseases.

There is an urgent need for new methods in the cure of biofilm-associated infections. For instance, cyclic di-GMP (c-di-GMP) is a commonly protected prokaryotic second messenger signal molecule necessary for biofilm development [58]. New inhibitors of diguanylate cyclase enzymes were identified by using in silico screening, and they tested them successfully in vitro. Inhibitors of flow pumps can also be recommended to complement the effect of antimicrobial agent and needed to be tested in vivo.

The choice of antimicrobial agents also seems to be significant because some of them may act as agonists for biofilm formation and some may disrupt it. The usage and dosages of novel antibiotics should be checked and clinically synthesized antibiotics should be tested at impactful concentrations by considering their distribution in biofilms and the detrimental effects of signaling molecules. Other compounds act as key enzymes in the biosynthesis of these signaling molecules and play a role in regulating virulence factor production and biofilm formation. A ligand-based strategy will allow the identification of new inhibitors in the future.

Better usage of the new active molecules can be supported by understanding mechanisms of antimicrobial agents activity as well as the molecular mechanisms associated with biofilm formation and recalcitrance [5].

### **4. Conclusion**

Biofilm infections are highly resistant to antibiotics and physical treatments and it is known that there are many strategies that support biofilm antibiotic resistance and tolerance, such as persistent cells, adaptive responses, and limited antibiotic penetration. It is also known that the underlying mechanisms of antibiotic tolerance and resistance in biofilms have a genetic basis in many cases.

In human diseases, highly organized bacterial cells gradually induce immune responses to form biofilms responsible for chronic infections that lead to tissue damage and permanent pathology. Therefore, the formation of biofilm is considered a critical concern in health care services.

Exploring promising cure methods for biofilm-associated infections is an urgent task. Few innovative and effective antibiotic strategies have been tried, such as dispersion of biofilms, antibiotic combinations with quorum sensing inhibitors, and a mixture of all these new techniques. Although the mentioned anti-biofilm strategies are important research areas, they are still in infancy and have not undergone clinical research and entered the commercial market. We hope that new anti-biofilm molecules based on finding universal substances that do not harm cells and synergistic with commonly used antibiotics will be available in the near future.

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**Author details**

provided the original work is properly cited.

Cukurova University, Adana, Turkey

Sadık Dincer\*, Fatima Masume Uslu and Anil Delik

\*Address all correspondence to: sdincer@cu.edu.tr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Antibiotic Resistance in Biofilm*

*DOI: http://dx.doi.org/10.5772/intechopen.92388*

### **Conflict of interest**

The authors declare no conflict of interest.

*Antibiotic Resistance in Biofilm DOI: http://dx.doi.org/10.5772/intechopen.92388*

*Bacterial Biofilms*

tested in vivo.

**4. Conclusion**

otic diffusion in these chronic diseases.

associated with biofilm formation and recalcitrance [5].

and resistance in biofilms have a genetic basis in many cases.

ered a critical concern in health care services.

The authors declare no conflict of interest.

Considering the rising number of antibiotic-resistant pathogens, QS inhibitors can be used as a mixture with the remaining sensitive antibiotics to complement their effects. These molecules mainly act by suppressing the QS system, and their practice with antibiotics leads to effective cure at much lower dosages of the drug than necessary, which may result in reduced therapeutic costs. These combinations can be beneficial in the cure of chronic infections, such as chronic urinary tract, cystic fibrosis, or prosthetic infections and biofilms are a barrier to antibi-

There is an urgent need for new methods in the cure of biofilm-associated infections. For instance, cyclic di-GMP (c-di-GMP) is a commonly protected prokaryotic second messenger signal molecule necessary for biofilm development [58]. New inhibitors of diguanylate cyclase enzymes were identified by using in silico screening, and they tested them successfully in vitro. Inhibitors of flow pumps can also be recommended to complement the effect of antimicrobial agent and needed to be

The choice of antimicrobial agents also seems to be significant because some of them may act as agonists for biofilm formation and some may disrupt it. The usage and dosages of novel antibiotics should be checked and clinically synthesized antibiotics should be tested at impactful concentrations by considering their distribution in biofilms and the detrimental effects of signaling molecules. Other compounds act as key enzymes in the biosynthesis of these signaling molecules and play a role in regulating virulence factor production and biofilm formation. A ligand-based strategy will allow the identification of new inhibitors in the future. Better usage of the new active molecules can be supported by understanding mechanisms of antimicrobial agents activity as well as the molecular mechanisms

Biofilm infections are highly resistant to antibiotics and physical treatments and it is known that there are many strategies that support biofilm antibiotic resistance and tolerance, such as persistent cells, adaptive responses, and limited antibiotic penetration. It is also known that the underlying mechanisms of antibiotic tolerance

In human diseases, highly organized bacterial cells gradually induce immune responses to form biofilms responsible for chronic infections that lead to tissue damage and permanent pathology. Therefore, the formation of biofilm is consid-

Exploring promising cure methods for biofilm-associated infections is an urgent task. Few innovative and effective antibiotic strategies have been tried, such as dispersion of biofilms, antibiotic combinations with quorum sensing inhibitors, and a mixture of all these new techniques. Although the mentioned anti-biofilm strategies are important research areas, they are still in infancy and have not undergone clinical research and entered the commercial market. We hope that new anti-biofilm molecules based on finding universal substances that do not harm cells and synergistic with commonly used antibiotics will be available

**142**

in the near future.

**Conflict of interest**
