Biofilms are the leading cause of nosocomial infections (about 60-70%).

This
makes it only imperative to address it. Quorum quenching, as the name implies,
involves interfering with quorum sensing with its inhibitors. There are several
mechanisms for quorum quenching. These are: inhibition of signal molecule synthesis,
using competing signal molecules (or receptor analogues), blocking signal transduction,
and enzymatic degradation of signal molecules. Signal molecules can be acyl
homoserine lactone for gram negative, oligopeptides for gram positive, and furan borate
diesters (or autoinducer 2) for both gram negative and positive.

Autoinducers 2 are known to be the universal communication molecule since it

mediates the communication between gram positive and negative bacteria.
Furthermore, the article of Brackman & Coenye (2015) described the lack of specific
enzymatic quenchers for autoinducer 2. The only known quorum quenching method
was via the monoclonal antibodies produced by the immune system. This paper focuses
on the enzymatic degradation of furan borate diesters (or autoinducer 2).

Weiland-Bräuer et al. (2016) constructed large-insert metagenomic libraries and

screened it for QS interfering activities. They found 13 metagenomic clones to interfere
with autoinducer-2. These showed homologies with bacterial oxidoreductases,
proteases, amidases, and aminotransferases. Of these, oxidoreductase was found to be
effective; it inhibited the biofilm formation of Klebsiella oxytoca M5a1 in a continuous
flow cell system and Klebsiella pneumoniae isolates from patients. This oxidoreductase
modified the signal molecule thereby inhibiting the biofilm formation of both species.
Further discovery of QS inhibitory molecules using metagenomic data was done
again by Weiland-Brauer, Malek, & Schmitz (2019), but this time, on Candida albicans
and Staphylococcus epidermidis -- both of which are opportunistic pathogens. Two
enzymes were found to be effective in inhibiting yeast-to-hyphae transitions of C.
albicans leading to impaired biofilm formation. These two enzymes were also effective
against the biofilm formation of S. epidermidis. Particularly, it repressed the synthesis of
adhesin, an important material for staphylococcal biofilm formation. However, this was
only tested on single-species biofilms although it shows potential on inhibiting
multi-species infections.

Another kind of enzyme is dioxygenase. In the study of Wullich et al. (2019),

quinolone dioxygenases open the quorum sensing signals of the P. aeruginosa (PQS)
ring and form N-octanyl-anthranilic acid and carbon monoxide, ultimately inhibiting it.
This study was more on analyzing the crystal structure of the dioxygenase alone and in
complex with PQS. The structure paved the way for the analysis of how the
dioxygenase disables the PQS. The dioxygenase was obtained from another bacteria,
Mycobacteroides abscessus.

LsrK, a kinase required for the signal transduction in AI-2, was used as a quorum
quencher delivered via a capsule by Rhoads et al. (2018). Aside from LsrK, it has a
substrate (ATP) for the enzymatic alteration of AI-2. The capsules were introduced in
bacteria. It resulted in the alteration of AI-2 communication, leading to the lowered
phenotypes related to QS. This proved to be effective in reducing biofilms and proposed
a way of inhibiting biofilms in humans.

This paper provided recent mechanisms on inhibiting biofilm formation of

clinically relevant bacteria. The biofilm formation of Klebsiella, Staphylococcus, and
Pseudomonas were successfully inhibited. This was successful on the fungi, Candida
albicans, as well. Furthermore, the last QS inhibitor provided a way of applying these
findings on humans.

References

Brackman, G., & Coenye, T. (2015). Quorum sensing inhibitors as anti-biofilm agents.
Current pharmaceutical design, 21(1), 5-11.
Marques, J. C., Lamosa, P., Russell, C., Ventura, R., Maycock, C., Semmelhack, M. F.,
... & Xavier, K. B. (2011). Processing the interspecies quorum-sensing signal
autoinducer-2 (AI-2): characterization of phospho-(S)-4, 5-dihydroxy-2,
3-pentanedione isomerization by LsrG protein. Journal of Biological Chemistry,
286(20), 18331-18343.

Rhoads, M. K., Hauk, P., Terrell, J., Tsao, C. Y., Oh, H., Raghavan, S. R., ... & Bentley,
W. E. (2018). Incorporating LsrK AI‐2 quorum quenching capability in a
functionalized biopolymer capsule. Biotechnology and bioengineering, 115(2),
278-289.

Weiland-Bräuer, N., Kisch, M. J., Pinnow, N., Liese, A., & Schmitz, R. A. (2016). Highly
effective inhibition of biofilm formation by the first metagenome-derived AI-2
quenching enzyme. Frontiers in microbiology, 7, 1098.

Weiland-Bräuer, N., Malek, I., & Schmitz, R. A. (2019). Metagenomic quorum quenching
enzymes affect biofilm formation of Candida albicans and Staphylococcus
epidermidis. PLoS One, 14(1), e0211366.

Wullich, S. C., Kobus, S., Wienhold, M., Hennecke, U., Smits, S. H., & Fetzner, S.
(2019). Structural basis for recognition and ring-cleavage of the Pseudomonas
quinolone signal (PQS) by AqdC, a mycobacterial dioxygenase of the
α/β-hydrolase fold family. Journal of structural biology, 207(3), 287-294.