Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury

Abstract

Classical antimicrobial drugs target proliferation and therefore place microbes under extreme selective pressure to evolve resistance. Alternative drugs that target bacterial virulence without impacting survival directly offer an attractive solution to this problem, but to date few such molecules have been discovered. We previously discovered a widespread group of bacterial adhesins, termed Multivalent Adhesion Molecules (MAMs) that are essential for initial binding of bacteria to host tissues and virulence. Thus, targeting MAM-based adherence is a promising strategy for displacing pathogens from host tissues and inhibiting infection. Here, we show that topical application of polymeric microbeads functionalized with the adhesin MAM7 to a burn infected with multidrug-resistant Pseudomonas aeruginosa substantially decreased bacterial loads in the wound and prevented the spread of the infection into adjacent tissues. As a consequence, the application of this adhesion inhibitor allowed for vascularization and wound healing, and maintained local and systemic inflammatory responses to the burn. We propose that MAM7-functionalized microbeads can be used as a topical treatment, to reduce bacterial attachment and hence prevent bacterial colonization and infection of wounds. As adhesion is not required for microbial survival, this anti-infective strategy has the potential to treat multidrug-resistant infections and limit the emergence of drug-resistant pathogens.

Bacterial infection imaging with [ 18 F]fluoropropyl-trimethoprim

“…2B). The prime mechanism of P. aeruginosa resistance to TMP is due to small-molecule export pump (11,27). Small-molecule efflux is most consistent with a lower overall level of uptake at saturation; however, we cannot exclude that an altered K i for Pseudomonas dhfr is also involved and could contribute to the delayed uptake.…”

“…TMP has nanomolar affinity for dhfr whereas it has micromolar affinity for human dihydrofolate reductase (DHFR) and is known to be amenable to synthetic modifications without loss of affinity (8)(9)(10). Thus, we developed a TMP-based radiotracer, [ 18 F]fluoropropyl-trimethoprim, or [ 18 F]FPTMP, tested its uptake in mammalian and bacterial cells in vitro, and tested in vivo its ability to identify common pathogenic bacteria such as Staphylococcus aureus, Escherichia coli, as well as Pseudomonas aeruginosa, which uses an efflux pump as a mechanism of antibiotic resistance (11). Additionally, we tested [ 18 F]FPTMP in a nonhuman primate to shed light on the expected human tissue biodistribution if this radiotracer were to be used for noninvasive diagnosis of bacterial infections in patients.…”

Acinetobacter : an emerging pathogen with a versatile secretome

“…Anti-virulence drugs could be a promising alternative to conventional antibiotic therapies. By targeting the virulence factors of a pathogen rather than their ability to growth, less pressure is exerted on microbes to develop resistance 11 . Recently, trials have begun to develop anti-virulence drugs with targets that include proteases, bacterial adhesins, and transcription factors, such as LysR 11 – 13 .…”

“…By targeting the virulence factors of a pathogen rather than their ability to growth, less pressure is exerted on microbes to develop resistance 11 . Recently, trials have begun to develop anti-virulence drugs with targets that include proteases, bacterial adhesins, and transcription factors, such as LysR 11 – 13 . As for Acinetobacter , despite the knowledge that has been compiled over the past decade about its pathogenesis, still little is known about its virulence attributes and how they are employed to cause disease.…”

3-Sulfogalactosyl–dependent adhesion of Escherichia coli HS multivalent adhesion molecule is attenuated by sulfatase activity

“…The Vibrio parahemolyticus MAM (MAM7) has been shown to bind phosphatidic acids, anionic lipids found at the host membrane, and to use the extracellular matrix protein fibronectin as a co-receptor ( 19 ). It was further shown that MAM7 binding to host cells competitively precludes other bacteria from adhering ( 17 , 20 ) and that this could be utilized as a strategy to combat infection in vivo ( 21 ). Our recent work showed that binding of the MAM homolog from the commensal E. coli HS (or short, MAM HS ) could also competitively inhibit bacterial attachment to host cells ( 22 ).…”