1. Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics
Martti Vaara Molecules . 2019 Jan 11;24(2):249. doi: 10.3390/molecules24020249.
Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well asAcinetobacter baumanniiandPseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized "permeabilizer" derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up.
2. SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells
Yaqian Liu, Lanlan Xu, Yong Wu, Zubair Hussain, Zehao Li, Pengfei She, Yimin Li, Shasha Liu Front Cell Infect Microbiol . 2022 Mar 18;12:858606. doi: 10.3389/fcimb.2022.858606.
Klebsiella pneumoniaehas emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistantK. pneumoniae.Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination usingin vitrocheckerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistantK. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistantK. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cellsin vitroand demonstrate considerable efficacy and low toxicityin vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistantK. pneumoniae-related infections.
3. Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741
Tara Langley, Kirsty Skinner, Alain Dorali, Peter Warn, Stephen Birchall, Emily Trimby, David Corbett, Martti Vaara, Jennifer Williams, Stephanie Sandiford, Troy Lister, Andrew Wise Antimicrob Agents Chemother . 2017 Jul 25;61(8):e00200-17. doi: 10.1128/AAC.00200-17.
Novel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed thein vitroefficacies of combinations of SPR741 with conventional antibiotics againstEscherichia coli,Klebsiella pneumoniae, andAcinetobacter baumanniiOf 35 antibiotics tested, the MICs of 8 of them were reduced 32- to 8,000-fold againstE. coliandK. pneumoniaein the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. AgainstA. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates ofE. coliandK. pneumoniaeand 17 additionalA. baumanniiisolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump inE. coli, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.
