SPR741 / Spero Therap - LARVOL DELTA

Antibiotics and non-traditional antimicrobial agents for pseudomonas aeruginosa in clinical phases 1, 2, and 3 trials. (PubMed, Expert Opin Investig Drugs) - "Traditional agents in clinical development include β-lactam/β-lactamase inhibitors (funobactam, taniborbactam, QPX2014-xeruborbactam), aminoglycosides (apramycin), polymyxin derivatives (upleganan, MRX-8, and SPR741), fluoroquinolones (MP-376), and lipopolysaccharide transport inhibitors (murepavadin). Non-traditional antibiotics in clinical development include anti-virulence agents (fluorothiazinone), monoclonal antibodies (INFEX-702, TRL-1068, and CMTX-101), bacteriophages (AP-PA02, YPT-01, BX004-A, and WRAIR-PAM-CF1), and miscellaneous agents (AR-501, PLG-0206, SNSP-113, OligoG CF-5/20, and ALX-009). A considerable number of antimicrobial agents, some with novel mechanisms of action, are in clinical phases of development for treating Pseudomonas aeruginosa infections. The urgent need for more therapeutic options necessitates the rapid optimization of progress to introduce new agents into clinical practice."

Journal • Review • Infectious Disease

Triple combination of SPR741, clarithromycin, and erythromycin against Acinetobacter baumannii and its tolerant phenotype. (PubMed, J Appl Microbiol) - "Collectively, these results reveal the potential of SPR741 in combination with clarithromycin and erythromycin as a clinical therapy for refractory infections caused by XDR A. baumannii."

Journal • Infectious Disease

Identification of a small molecule 0390 as a potent antimicrobial agent to combat antibiotic-resistant Escherichia coli. (PubMed, Front Microbiol) - "To confront the issue of the infectious diseases related to E. coli and its multidrug resistant strains, potential approaches, such as new antibacterial agents with different structures from conventional antibiotics and drug combinations, are urgently needed. In this study, we have determined the in vitro and in vivo antimicrobial potential of 0390 alone or in combination with SPR741, which might be used as a treatment option for E. coli related infections."

Journal • Infectious Disease

Minocycline and the SPR741 Adjuvant Are an Efficacious Antibacterial Combination for Acinetobacter baumannii Infections. (PubMed, Antibiotics (Basel)) - "Previously, we showed that SPR741 had this adjuvant effect with regard to rifampin; however, rifampin is often not used clinically because of easily acquired resistance. To find additional, appropriate clinical partners for SPR741 with respect to pulmonary and wound infections, we investigated tetracyclines and found a previously undocumented synergy with minocycline in vitro and in vivo in murine models of infection."

Journal • Infectious Disease • Pneumonia

Antibacterial activity of metergoline analogues and investigations into their mechanisms of action (ACS-Fall 2022) - "Arylacrylamide derivatives were inactive against wild-type Gram-negative bacteria but their potencies were improved considerably (up to >128-fold) in combination with outer-membrane permeabilizer SPR741. Metergoline analogues also retained activity against multidrug-resistant strains of Staphylococcus aureus, suggesting a mechanism of action that is distinct from clinically used antibiotic classes."

Dermatology • Infectious Disease

SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells. (PubMed, Front Cell Infect Microbiol) - "These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells in vitro and demonstrate considerable efficacy and low toxicity in 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-resistant K. pneumoniae -related infections."

Journal • Infectious Disease • Pneumonia

Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery. (PubMed, ACS Med Chem Lett) - "Arylacrylamide analogues of metergoline show modest activity against wild-type (WT) Gram-negative bacteria but are more active against strains of efflux-deficient S. Tm and hyperpermeable Escherichia coli. The potencies against WT strains of E. coli, Acinetobacter baumannii, and Burkholderia cenocepacia are also improved considerably (up to >128-fold) with the outer-membrane permeabilizer SPR741, suggesting that the ergot scaffold represents a new lead for the development of new antibiotics."

Journal • Dermatology • Infectious Disease

The cathelicidin-derived close-to-nature peptide D-11 sensitizes Klebsiella pneumoniae to a range of antibiotics in vitro, ex vivo and in vivo. (PubMed, Int J Antimicrob Agents) - "The results show that the peptide D-11 displays strong synergistic activity with several antibiotics belonging to different families, in particular against Klebsiella pneumoniae, even better than some other outer membrane-active peptides that are currently in a clinical trial such as SPR741. Notably, we observed this activity in vitro, ex vivo in a newly designed bacteremia model and in vivo in a mice abscess infection model. Overall, our results suggest that D-11 is a good candidate to repurpose the activity of traditional antibiotics against Klebsiella pneumoniae."

Journal • Preclinical • Infectious Disease • Pneumonia

In vitro activity analysis of a new generation polymyxin, SPR741, tested in combination with antimicrobial agents against a challenge set of Enterobacteriaceae, including molecularly characterized strains. (PubMed, Antimicrob Agents Chemother) - "The activity of azithromycin, fusidic acid, vancomycin, doxycycline and minocycline were evaluated alone and in combination with SPR741. Azithromycin-SPR741 MIC (MIC, 1/16 mg/L) against isolates with enzymatic MLS mechanisms was lower than those with ribosomal protection (MIC, 16/>32 mg/L). SPR741 increased the in vitro activity of tested co-drugs in different levels and seemed to be dependent on species and resistance mechanisms of the respective co-drug."

Combination therapy • Journal • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Outer membrane interaction kinetics of new polymyxin B analogs in Gram-negative bacilli. (PubMed, Antimicrob Agents Chemother) - "In this study, polymyxin analogs designed to have reduced nephrotoxicity, direct activity, and potentiating activity were assessed for inhibition and outer membrane interaction kinetics against wild-type (WT) and polymyxin or multidrug-resistant (MDR) Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae In MIC assays, two polymyxin B (PMB) analogs (SPR1205 and SPR206) and a polymyxin E analog (SPR946), with shortened peptide side chains and branched aminobutyryl N termini, exhibited promising activity compared with PMB and previously tested control polymyxin analogs SPR741 and polymyxin B nonapeptide (PMBN). Moreover, Hill numbers were greater than 1 for most of the compounds tested on E. coli and P. aeruginosa strains which indicates that the disruption of the outer membrane by one molecule of compound cooperatively enhance the subsequent interactions of other molecules against WT and MDR strains. The high activity demonstrated by..."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases