MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: Highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate

Active efflux confers intrinsic resistance to multiple antibiotics in Pseudomonas aeruginosa, including old disused molecules. Beside resistance, intracellular survival is another reason for failure to eradicate bacteria with antibiotics. We evaluated the capacity of polyaminoisoprenyl potentiators (designed as efflux pump inhibitors [EPIs]) NV716 and NV731 compared to PAβN to restore the activity of disused antibiotics (doxycycline, chloramphenicol [substrates for efflux], rifampin [not substrate]) in comparison with ciprofloxacin against intracellular P. aeruginosa (strains with variable efflux levels) in THP-1 monocytes exposed during 24h to antibiotics alone (0.003-100x MIC) or combined with EPIs. Pharmacodynamic parameters (apparent static concentrations [Cs]; maximal relative efficacy [Emax]) were calculated using the Hill equation of concentration-response curves. PAβN and NV731 moderately reduced (0-4 doubling dilutions) antibiotic MICs but did not affect their intracellular activity. NV716 markedly reduced (1-16 doubling dilutions) the MIC of all antibiotics (substrates or not for efflux; strains expressing efflux or not); it improved their relative potency and maximal efficacy (lower Cs; more negative Emax) intracellularly. In parallel, NV716 reduced the persister fraction in stationary cultures when combined with ciprofloxacin. In contrast to PAβN and NV731 that act as EPIs against extracellular bacteria only, NV716 can resensitize P. aeruginosa to antibiotics whether substrates or not for efflux, both extracellularly and intracellularly. This suggests a complex mode of action that goes beyond a simple inhibition of efflux and reduces bacterial persistence. NV716 may appear as a useful adjuvant, including to disused antibiotics with low antipseudomonal activity, to improve their activity, including against intracellular P. aeruginosa.

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The effect of efflux pump inhibitors on in vitro and in vivo efficacy of solid lipid nanoparticles containing SN38

Journal of Drug Delivery Science and Technology ◽

10.1016/j.jddst.2020.101969 ◽

2020 ◽

Vol 60 ◽

pp. 101969

Author(s):

Samira Nasirizadeh ◽

Mahmoud Reza Jaafari ◽

Mehrdad Iranshahi ◽

Shiva Golmohammadzadeh ◽

Asma Mahmoudi ◽

...

Keyword(s):

Solid Lipid Nanoparticles ◽

Efflux Pump ◽

Lipid Nanoparticles ◽

In Vivo Efficacy ◽

Solid Lipid ◽

Efflux Pump Inhibitors

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Peptidomimetics of Efflux Pump Inhibitors Potentiate the Activity of Levofloxacin in Pseudomonas aeruginosa

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(02)00006-9 ◽

2002 ◽

Vol 12 (5) ◽

pp. 763-766 ◽

Cited By ~ 47

Author(s):

Thomas E. Renau ◽

Roger Léger ◽

Rose Yen ◽

Miles W. She ◽

Eric M. Flamme ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Efflux Pump Inhibitors

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MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2004.03.007 ◽

2004 ◽

Vol 14 (10) ◽

pp. 2493-2497 ◽

Cited By ~ 31

Author(s):

Kiyoshi Nakayama ◽

Noriko Kuru ◽

Masami Ohtsuka ◽

Yoshihiro Yokomizo ◽

Atsunobu Sakamoto ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Acrylic Acid ◽

Efflux Pump ◽

Acid Moiety ◽

Efflux Pump Inhibitors ◽

Poor Stability

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Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(01)00033-6 ◽

2001 ◽

Vol 11 (5) ◽

pp. 663-667 ◽

Cited By ~ 33

Author(s):

Thomas E Renau ◽

Roger Léger ◽

Eric M Flamme ◽

Miles W She ◽

Carla L Gannon ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Efflux Pump Inhibitors ◽

The Stability

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Pan-β-Lactam Resistance Development in Pseudomonas aeruginosa Clinical Strains: Molecular Mechanisms, Penicillin-Binding Protein Profiles, and Binding Affinities

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00680-12 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4771-4778 ◽

Cited By ~ 83

Author(s):

Bartolomé Moyá ◽

Alejandro Beceiro ◽

Gabriel Cabot ◽

Carlos Juan ◽

Laura Zamorano ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Molecular Mechanisms ◽

Efflux Pump ◽

Binding Protein ◽

Efflux Pumps ◽

Binding Affinities ◽

Penicillin Binding Protein ◽

Content Type ◽

Reverse Transcription Pcr

ABSTRACTWe investigated the mechanisms leading toPseudomonas aeruginosapan-β-lactam resistance (PBLR) development during the treatment of nosocomial infections, with a particular focus on the modification of penicillin-binding protein (PBP) profiles and imipenem, ceftazidime, and ceftolozane (former CXA-101) PBP binding affinities. For this purpose, six clonally related pairs of sequential susceptible-PBLR isolates were studied. The presence ofoprD,ampD, anddacBmutations was explored by PCR followed by sequencing and the expression ofampCand efflux pump genes by real-time reverse transcription-PCR. The fluorescent penicillin Bocillin FL was used to determine PBP profiles in membrane preparations from all pairs, and 50% inhibitory concentrations (IC50s) of ceftolozane, ceftazidime, and imipenem were analyzed in 3 of them. Although a certain increase was noted (0 to 5 2-fold dilutions), the MICs of ceftolozane were ≤4 μg/ml in all PBLR isolates. All 6 PBLR isolates lacked OprD and overexpressedampCand one or several efflux pumps, particularlymexBand/ormexY. Additionally, 5 of them showed modified PBP profiles, including a modified pattern (n= 1) or diminished expression (n= 1) of PBP1a and a lack of PBP4 expression (n= 4), which correlated with AmpC overexpression driven bydacBmutation. Analysis of the essential PBP IC50s revealed significant variation of PBP1a/b binding affinities, both within each susceptible-PBLR pair and across the different pairs. Moreover, despite the absence of significant differences in gene expression or sequence, a clear tendency toward increased PBP2 (imipenem) and PBP3 (ceftazidime, ceftolozane, imipenem) IC50s was noted in PBLR isolates. Thus, our results suggest that in addition to AmpC, efflux pumps, and OprD, the modification of PBP patterns appears to play a role in thein vivoemergence of PBLR strains, which still conserve certain susceptibility to the new antipseudomonal cephalosporin ceftolozane.

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