Lectin-Targeted Prodrugs Activated by Pseudomonas aeruginosa for Self-Destructive Antibiotic Release

Abstract

Chronic Pseudomonas aeruginosa infections are characterized by biofilm formation, a major virulence factor of P. aeruginosa and cause of extensive drug resistance. Fluoroquinolones are effective antibiotics but are linked to severe side effects. The two extracellular P. aeruginosa-specific lectins LecA and LecB are key structural biofilm components and can be exploited for targeted drug delivery. In this work, several fluoroquinolones were conjugated to lectin probes by cleavable peptide linkers to yield lectin-targeted prodrugs. Mechanistically, these conjugates therefore remain non-toxic in the systemic distribution and will be activated to kill only once they have accumulated at the infection site. The synthesized prodrugs proved stable in the presence of host blood plasma and liver metabolism but rapidly released the antibiotic cargo in the presence of P. aeruginosa in a self-destructive manner in vitro. Furthermore, the prodrugs showed good absorption, distribution, metabolism, and elimination (ADME) properties and reduced toxicity in vitro, thus establishing the first lectin-targeted antibiotic prodrugs against P. aeruginosa.

Insights on Pseudomonas aeruginosa Carbohydrate Binding from Profiles of Cystic Fibrosis Isolates Using Multivalent Fluorescent Glycopolymers Bearing Pendant Monosaccharides

“…It should also be respected in therapeutics design that, as discussed above, the varied permutations of the condition of the host, as well as the adaptations of the colonizing microbes and the treatments being received, are likely to keep the infectious landscape ever-changing [8,20,43,133]. The P. aeruginosa variability and fluidity in the expression or lack of expression of virulence features and structures are expected to complicate the development of targeted agents [10,11,15,20,24,26,29,36,58,63,88,90,116,117,131,136]. The distinctions and differences in complex mucosal glycoconjugates are anticipated in CF respiratory tracts and are mechanistically important to bacterial binding and/or clearance [9,60,65,67,78,79,81,82].…”

“…Anti-adhesives designed to interfere with the functions of bacterial carbohydrate-binding proteins (lectins) may limit and/or disrupt bacterial lectin-host interactions, bacterial aggregation, and lectin-biofilm matrix associations [12,22,27,35,52,55,57,[59][60][61]. The specific targeting of antimicrobial agents to bacterial biofilms, as suggested by recent investigations, may also be possible [22,54,59,[62][63][64], and not only aid in achieving appropriate therapeutic dosages where needed in the CF airway, but also benefit and guide efforts toward antibiotic stewardship.…”

“…To target P. aeruginosa cellular and extracellular carbohydrate interactions, many types of glycomimetics and multivalent glycoconjugates have been suggested as potential anti-infectives and are in various stages of investigation [44,52,54,55,57,59,61,105,106,[108][109][110][111]. Emphasizing the inhibition of the binding of the Pseudomonas lectins, examples include small molecule glycomimetics, glycoclusters, heteroglycoclusters, heteromultivalent gold nanorods, glycodendrimers, glycopolymers, aromatic thioglycosides, glyconanoparticles, and nanotherapeutics with glycomimetic shells [25,52,55,57,61,63,97,[103][104][105][106][107][109][110][111][112][113]. Bioavailable, monovalent, lowmolecular-weight glycomimetic inhibitors of LecB were shown to inhibit biofilm formation, illustrating the potential for this strategy as a new class of antimicrobial drugs [114].…”

Glycomimetics for the inhibition and modulation of lectins

“…In a follow-up report, the linker was varied and the tetrapeptide sequence Gly-Ala-Leu-Ala was implemented as a scission motif for pathogen-specific activation by the secreted bacterial protease LasB to liberate the free drug at the infection site. 723 The resulting conjugates 192–195 have been analysed for their degradation kinetics in various matrices and their antimicrobial activity. While all conjugates were stable in human blood plasma in vitro , they were rapidly cleaved in the presence of a P. aeruginosa culture supernatant containing the activating enzyme LasB.…”

The Benefits and Challenges of Antibiotics–Non-Steroidal Anti-Inflammatory Drugs Non-Covalent Reaction

“…Also, more than half of S. aureus strains tested were MDR, showing resistance to fluoroquinolones [126][127][128]. Efforts have been made to improve the fluoroquinolones' potency, for example, by conjugate biofilm formation, a major virulence factor of Pseudomonas auroginosa that causes antibiotic resistance [129].…”