Polyamino-Isoprenic Derivatives Block Intrinsic Resistance of P. aeruginosa to Doxycycline and Chloramphenicol In Vitro

Abstract

Multidrug resistant bacteria have been a worldwide concern for decades. Though new molecules that effectively target Gram-positive bacteria are currently appearing on the market, a gap remains in the treatment of infections caused by Gram-negative bacteria. Therefore, new strategies must be developed against these pathogens. The aim of this study was to select an antibiotic for which a bacterium is naturally resistant and to use an escort molecule to restore susceptibility, similarly to the model of β-lactam/ β-lactamase inhibitors. High-content screening was performed on the reference strain PA01, allowing the selection of four polyamino-isoprenic compounds that acted synergistically with doxycycline. They were assayed against clinical isolates and Multi-Drug-Resistant strains. One of these compounds was able to decrease the MIC of doxycycline on the reference strain, efflux pump overproducers and clinical isolates of P. aeruginosa, to the susceptibility level. Similar results were obtained using chloramphenicol as the antibiotic. Membrane permeation assays and real-time efflux experiments were used to characterize the mechanism of doxycycline potentiation.The results showed that the selected compound strongly decreases the efficiency of glucose-triggered efflux associated with a slight destabilization of the outer membrane. According to these data, targeting natural resistance may become an interesting way to combat MDR pathogens and could represent an alternative to already devised strategies.

6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers

“…18,19 To better understand whether 3 can act as a disruptor of the transmembrane potential, a real-time efflux assay was utilised. 20 This assay makes use of the membrane-potential-sensitive probe DiSC 3 (5), which when preloaded into bacteria, concentrates in the inner membrane and quenches its own fluorescence. Upon membrane depolarisation, the dye is released and an increase in fluorescence (measured in relative fluorescence units) is observed.…”

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates

“…However, enzymes capable of inactivating drugs are only one factor contributing to intrinsic drug resistance in bacteria. Other factors including membrane penetration, efflux mechanisms, and endogenous native substrate competition contribute to intrinsic drug resistance262728. The ability to improve susceptibility of M .…”

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…However, Yasuda et al demonstrated that polyamine compounds increase the permeability of the outer membrane of E. coli and potentiate antimicrobial activities of novobiocin and erythromycin, presumably by displacing divalent cations (Ca 2+ and Mg 2+ ) found in the membrane, thus altering its integrity. Although it was shown that geranylamine does not permeabilize the outer membrane, further studies of polyamino‐isoprene derivatives, which are structurally related to 66 and 67 , showed that these compounds tend to destabilize the P. aeruginosa outer membrane . Thus, the antibiotic potentiating activity of this class of EPIs may be due to both EPI and increased permeability of the outer membrane of E. coli , which could be connected to their cationic character at physiological pH.…”

“…Although it was shown that geranylamine does not permeabilize the outer membrane, 234 further studies of polyamino-isoprene derivatives, which are structurally related to 66 and 67, showed that these compounds tend to destabilize the P. aeruginosa outer membrane. 237 Thus, the antibiotic F I G U R E 1 8 Structures of hydantoins potentiating activity of this class of EPIs may be due to both EPI and increased permeability of the outer membrane of E. coli, which could be connected to their cationic character at physiological pH.…”