**Acknowledgements**

*Bacterial Biofilms*

Animals and Human

*+, yes; NC, not communicated.*

*Aminoglycosides.*

*ǂ*

*\**

*1*

*2 Ampicillin.*

**Table 1.**

Porcine kidney [50, 107]

Human and murine sera [109, 110]

*Solenopsis invicta* (insect; ant) [112]

*LuxR-type transcription factor of Agrobacterium tumefaciens.*

*Natural compounds inhibiting* P. aeruginosa *QS and biofilm formation.*

*Patulin alone does not affect the development of biofilm.*

**46**

**Figure 4.**

medicines [120].

entanglement between different QS systems, to the ability of *Pseudomonas* to compensate deficient systems and to the intervention of key actors involved in biofilm formation, outside of QS circuitry [12]. Millenia of coevolution between plants and bacteria have led to complex defense strategies, with plants producing cocktails of bioactive compounds with multiple targets [114] and/ or compounds such as terrein that impact dual inhibitory targets. In the current state of research, much remains to be done in understanding these mechanisms and the real impact of such combinations before arriving at a commercial use. Nevertheless, following a combined approach for "adjuvant antibiotherapy" and "combined antibiotherapy" will undeniably lead to a renewed concept of "complex drugs for complex diseases," a well-known presupposed in traditional

*objective lens and colored images were assembled using Adobe Photoshop.*

P. aeruginosa *biofilm phenotypes and effectiveness of tobramycin treatment in presence of dimethyl sulfoxide (DMSO 1%) or, cassipourol (CAS: 100 μM) or oleanolic aldehyde coumarate (OALC: 200 μM). (a) After 1 day of incubation,* P. aeruginosa *fails to form structured confluent aggregate in presence of CAS or OALC as compared to DMSO treatment. (b) CAS and OALC considerably increase the susceptibility of* P. aeruginosa *to tobramycin (100 μg/mL), as shown by the increased proportion of dead cells compared with DMSO. Similar results are observed when tobramycin is added simultaneously with CAS or OALC to one-day old untreated biofilms. The bacterial viability was assessed by staining the cells with SYTO-9 (green areas zones—live living bacteria) and propidium iodide (red areas zones—dead bacteria) furnished in the LIVE/DEAD BacLight kit. Cells were visualized using a LeicaDMIRE2 inverted fluorescence microscope using equipped with a 40×* 

**Origin Compounds (class) Target (QS) Synergy** 

Paraoxonases 1 Enzyme

(lactonase)

Type I acylase AHL

**with antibiotics**

NC

NC

degradation

AHL degradation

Solenopsin A (Alkaloid) *rhl* system NC

The authors would like to thank ARES (Académie de Recherche et d'Enseignement Supérieur, Belgium) for financial support throughout PRD projects.
