# 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 antib biofilm 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. biofilms; infection; inhibitors; extracellular polymeric substances; antimicrobials; small molecules +
Footnote †: journal: _microorganisms_  
**S.N.N. Escherichia coli_[22; 23], and _Proteus mirabilis_[24; 25]. Biofilm recalcitrance [26; 27; 28; 29; 30] is the potential of the microbes to sustain even in high concentrations of antibiotics, which leads to recurrence of infections and collapse of treatment. The microbes enclosed within the biofilm have proven to be more resistant towards classic antibiotic therapy in contrast to the planktonic cell population. This recalcitrance is revocable by disrupting the biofilm and reinstating the microbes to the planktonic state [31]. Patients with ingrained medical devices such as prosthetic heart valves, catheters, joint prosthesis, cardiac pacemakers, dental implants and contact lenses have utmost risk of biofilm-based nosocomial infections [32; 33; 34]. Such foreign bodies provide an exemplary surface for the adhesion of bacterial cells, which can be facilitated by non-specific factors such as shear forces, hydrophobicity and electrostatic interactions [35; 36; 37]. A common example of biofilms covering abiotic surfaces is their formation on dental restorative and implant materials, where oral bacteria adhere to hydrophobic and hydrophilic abiotic surfaces and biofilms accumulate more readily on rough than on smooth surfaces [38; 39]. This can result in periimplantitis, a destructive inflammatory process that affects the soft and hard tissues surrounding dental implants and may result in implant failure. There is a multitude of methods for decontaminating pathogenic microorganisms on dental implants [40]. Exposure of bacteria to concentrations of an antibiotic that are lower than the minimum inhibitory concentration (MIC), known as subinhibitory concentrations, can enforce a higher capacity for biofilm formation, which in turn can result in a decreased susceptibility to antibiotics [41; 42; 43; 44]. For example, subinhibitory antibiotic concentrations have recently been shown to enhance biofilm formation of clinical _Enterococcus faecalis_ isolates [45].