Development of Antibiofilm Therapeutics Strategies to Overcome Antimicrobial Drug Resistance

Abstract

A biofilm is a community of stable microorganisms encapsulated in an extracellular matrix produced by themselves. Many types of microorganisms that are found on living hosts or in the environment can form biofilms. These include pathogenic bacteria that can serve as a reservoir for persistent infections, and are culpable for leading to a broad spectrum of chronic illnesses and emergence of antibiotic resistance making them difficult to be treated. The absence of biofilm-targeting antibiotics in the drug discovery pipeline indicates an unmet opportunity for designing new biofilm inhibitors as antimicrobial agents using various strategies and targeting distinct stages of biofilm formation. The strategies available to control biofilm formation include targeting the enzymes and proteins specific to the microorganism and those involved in the adhesion pathways leading to formation of resistant biofilms. This review primarily focuses on the recent strategies and advances responsible for identifying a myriad of antibiofilm agents and their mechanism of biofilm inhibition, including extracellular polymeric substance synthesis inhibitors, adhesion inhibitors, quorum sensing inhibitors, efflux pump inhibitors, and cyclic diguanylate inhibitors. Furthermore, we present the structure-activity relationships (SAR) of these agents, including recently discovered biofilm inhibitors, nature-derived bioactive scaffolds, synthetic small molecules, antimicrobial peptides, bioactive compounds isolated from fungi, non-proteinogenic amino acids and antibiotics. We hope to fuel interest and focus research efforts on the development of agents targeting the uniquely complex, physical and chemical heterogeneous biofilms through a multipronged approach and combinatorial therapeutics for a more effective control and management of biofilms across diseases.

Keywords: antimicrobials; biofilms; extracellular polymeric substances; infection; inhibitors; small molecules.

Figure 1

Biofilm formation process.

Figure 2

Chemical structures of some autoinducers (top) and production of virulence factors (bottom).

Figure 3

Major mechanisms involved in the development of antibiotic resistance among bacterial species.

Figure 4

Chemical structure of DMNP.

Figure 5

Chemical structures of potent 1,2,4-oxadiazole topsentin analogs.

Figure 6

Chemical structure of amide chalcones.

Figure 7

Chemical structure of cajaninstilbene acid derivatives.

Figure 8

Chemical structures of various quorum sensing inhibitors.

Figure 9

Chemical structures of some enzymatic cleavage inhibitors.

Figure 10

Chemical structures of some efflux pumps inhibitors.

Figure 11

Chemical structures of some quaternary ammonium compounds.

Figure 12

Chemical structures of some natural antibiofilm agents.

Figure 13

Investigative strategies to eradicate biofilms.

Figure 14

Mechanisms of antibiofilm activities of nanoparticles.