Group photo. From left to right: Xavier Daura, Sara Segura, Òscar Conchillo-Solé, Daniel Yero, Celeste Gómez, Xavier Coves, Belén Mahía, Pol Huedo, Marina Bataller and Isidre Gibert
Introduction and background
Stenotrophomonas maltophilia it is a metabolic and genetically diverse species that inhabits a wide range of environments, particularly in the rhizosphere, considered its main habitat in nature. He is the only member of the family Xanthomonadaceae known to be an opportunistic human pathogen. Its prevalence and global incidence have increased significantly in the last decade, especially in patients with cystic fibrosis (Hatziagorou et al., 2019). The threat it represents S. maltophilia for human health is its low susceptibility to almost all classes of antibiotics (Sánchez, 2015). For these reasons, it has been classified as one of the main multidrug-resistant organisms (MDR) in hospital settings, and has recently been included in the list of the ten priority resistant microorganisms in ICUs (Rello et al., 2019).
In S. maltophilia Several virulence factors have been recognized that could contribute to the colonization of human tissues, including, but not limited to, various extracellular enzymes and the formation of biofilm. It is known that S. maltophilia shape biofilm on a wide range of biotic and abiotic surfaces, including medical devices such as catheters, prosthetics, etc. The formation of biofilm facilitates bacterial persistence and resistance to the action of antimicrobials, which is why it has been considered a form of phenotypic resistance (Sánchez, 2015). As for many gram-negative bacteria, the system of quorum sensing (QS) has also been considered an important factor regulating virulence in S. maltophilia (Huedo et al., 2018). In general, QS systems are communication networks that coordinate bacterial populations and communities through molecules known as self-inducers (AI). These networks are one of the main mechanisms that control the pathogenesis of many clinically important species (Rutherford and Bassler, 2012). Study how these networks control aspects related to virulence, persistence and tolerance to antibiotics in S. maltophilia, is one of the objectives of our research group.
Scientific results of the group and future perspectives
In the main QS system of S. maltophilia The AI molecule is cis-11-methyl-2-dodecanoic fatty acid, known as DSF (from the English diffusible signal factor). The genes for the synthesis and perception of DSF, as well as the initiation of the regulatory cascade mediated by this signal, are part of a cluster called rpf. Our group has shown that in S. maltophilia Two sub-populations can be distinguished based on the differences in the sequence of this cluster (Huedo et al., 2014). These genotypic differences translate into significant functional diversity between strains of the type rpf-1 the rpf-2. For example, strains of type rpf-2 do not produce detectable levels of DSF under laboratory conditions and are more virulent in an animal model with nematodes. However, these strains are capable of producing their own DSF and activating QS-mediated mechanisms, when they perceive the DSF produced by strains. rpf-1 (Huedo et al., 2015). On the other hand, strains rpf-1 mutants in DSF synthase stop secreting DSF, produce more biofilm and they are less virulent (Huedo et al., 2014). All of this demonstrates that the coordination of DSF-mediated virulence in S. maltophilia it is more complex and multifactorial than previously thought.
More recently our group has shown, using a panel of 79 clinical strains, that strains of type rpf-2 are indeed more virulent in animal models, probably because they produce more biofilm. Surprisingly the type of cluster rpf it also influences the resistance profile of the strains, which makes us think about a connection between the QS system mediated by DSF and resistance to antibiotics. We know that one of the cluster variants rpf was acquired by S. maltophilia through horizontal transfer (Huedo et al., 2015), therefore, we do not rule out the hypothesis that resistance determinants have been acquired during these events. Our group is now immersed in studying in more depth the mechanism of QS mediated by DSF in S. maltophilia and identify the determinants of virulence and resistance that could be controlled by this system. To this end, we are studying the global expression of genes under culture conditions that activate QS systems, such as the start of the stationary phase or the presence of AI molecules. On the other hand, it is now known that S. maltophilia it has mechanisms to inhibit or degrade AI molecules secreted by other bacteria in its environment (Huedo et al., 2018), and we have evidence that some types of fatty acids can interfere with the DSF system of the cell itself (Huedo et al., 2015 ). All this has made us think of alternative antimicrobial strategies based on QS inhibition. The group also has the experience of bioinformaticians who participate in the search for those determinants that could be attractive targets to eliminate or inhibit these bacteria.
Regarding the search for antimicrobial strategies based on QS inhibition, our group has taken the first steps in collaboration with a group from University College Cork in Ireland (Huedo et al., 2019). In this work, chemical compounds based on the DSF molecule of S. maltophilia. Some of these molecules were able to interfere with cell-cell communication by altering the formation of biofilm and enhancing the activity of colistin, one of the last-resort antibiotics against MDR gram-negative pathogens. This proof of concept validates the strategy of interfering with bacterial QS to combat difficult-to-treat infections caused by MDR-forming organisms. biofilm. On the other hand, it opens a door in the search for strategies that enhance the effect of antibiotics such as colistin, for which more and more resistant strains are being detected. Our group has recently described that in S. maltophilia There is an almost generalized phenomenon of heteroresistance to colistin (Martínez-Servat et al., 2018). We have seen that in a population of cells susceptible to colistin, a subpopulation of highly resistant cells coexists or rapidly arises. Hetero-resistance to antibiotics is of great clinical significance because it is responsible for the failure of many treatments and the persistence of some infections. This resistant subpopulation also has a greater capacity to form biofilm, which reinforces our hypothesis as to whether the QS system and resistance to some antibiotics have elements in common in S. maltophilia.
Representative bibliography
Hatziagorou, E., Orenti, A., Drevinek, P., Kashirskaya, N., Mei-Zahav, M., De Boeck, K., et al. (2019). Changing epidemiology of the respiratory bacteriology of patients with cystic fibrosis-data from the European cystic fibrosis society patient registry. J. Cyst. Fibros. S1569-1993(19)30838-0.
Huedo, P., Coves, X., Daura, X., Gibert, I., and Yero, D. (2018). Quorum Sensing Signaling and Quenching in the Multidrug-Resistant Pathogen Stenotrophomonas maltophilia. Front Cell Infect Microbiol 8, 122.
Huedo, P., Kumar, V. P., Horgan, C., Yero, D., Daura, X., Gibert, I., et al. (2019). Sulfonamide-based diffusible signal factor analogs interfere with quorum sensing in Stenotrophomonas maltophilia and Burkholderia cepacia. Future Med Chem 11, 1565–1582.
Huedo, P., Yero, D., Martínez-Servat, S., Estibariz, I., Planell, R., Martínez, P., et al. (2014). Two different rpf clusters distributed among a population of Stenotrophomonas maltophilia clinical strains display differential diffusible signal factor production and virulence regulation. J. Bacteriol. 196, 2431–2442.
Huedo, P., Yero, D., Martinez-Servat, S., Ruyra, À., Roher, N., Daura, X., et al. (2015). Decoding the genetic and functional diversity of the DSF quorum-sensing system in Stenotrophomonas maltophilia. Front Microbiol 6, 761.
Martínez-Servat, S., Yero, D., Huedo, P., Marquez, R., Molina, G., Daura, X., et al. (2018). Heterogeneous Colistin-Resistance Phenotypes Coexisting in Stenotrophomonas maltophilia Isolates Influence Colistin Susceptibility Testing. Front Microbiol 9, 2871.
Rello, J., Kalwaje Eshwara, V., Lagunes, L., Alves, J., Wunderink, R. G., Conway-Morris, A., et al. (2019). A global priority list of the TOp TEn resistant Microorganisms (TOTEM) study at intensive care: a prioritization exercise based on multi-criteria decision analysis. Eur. J. Clin. Microbiol. Infect. Dis. 38, 319–323.
Rutherford, S. T., and Bassler, B. L. (2012). Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med. 2, a012427.
Sánchez, M. B. (2015). Antibiotic resistance in the opportunistic pathogen Stenotrophomonas maltophilia. Front Microbiol 6, 658.