Abstract:While individually inefficient against Gram-negative bacteria, in-vitro combinations of rifampin and OAK were mutually synergistic since sub-minimal inhibitory concentrations of one compound have potentiated the other by 2–4 orders of magnitude. Synergy persisted in-vivo as single-dose systemic treatment of Klebsiella infected mice resulted in 10–20% versus 60% survival, respectively accomplished by individual and combined compounds. This outcome was achieved without drug formulation, rather, pharmacokinetic c… Show more
“…In summary, while C 10 OOc 12 O was previously proposed to sensitize GNB to host plasma antibacterial proteins (29), the present study provides evidence for the MAC's capacity to perform much better in the presence of an antibiotic, bestowing potent antibacterial activity onto virtually inactive endogenous and/or exogenous compounds. In this sense, the current work ratifies the conclusions drawn in previous studies (20,28,29) that propose that the newly found antibacterial potencies are likely to stem from the damaged OM and/or CM, thereby supporting this approach's potential usefulness in the search of new alternatives to antibiotics.…”
Section: Enhancing In Vivo Efficacies Through Combination Therapiessupporting
confidence: 84%
“…However, data shown in Fig. 2B, as well as results from previous studies (18,28), argue against such a possibility. In fact, even less hydrophobic analogs (e.g., C 8 KKc 12 K) were able to damage the OM.…”
We recently reported the aptitude of a membrane-active lipopeptide (COOcO) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis-sepsis model for mono- and combination therapies. We found that by altering permeability of both outer and inner membranes, subinhibitory concentrations of COOcO can transiently sensitize GNB to diverse cytoplasm-targeting antibiotics in simple media. Sensitization was maintained in plasma, where COOcO instigated greater bactericidal activities, including in the presence of a bacteriostatic antibiotic (erythromycin). Single-dose administrations of rifampin and COOcO to -infected mice resulted in 55% 0, and 36% viability, respectively, for combined and individual treatments. Combining COOcO and erythromycin has similarly improved mice protection from developing fatal sepsis. Consequently, the data confirmed that COOcO renders GNB sensitive to both endogenous and exogenous antibacterials, and suggested that the tripartite concomitant presence increases therapeutic efficacy synergistically. This approach might expand the available treatment options to comprise antimicrobials with low permeability and/or efflux issues.-Jammal, J., Zaknoon, F., Mor, A. Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics.
“…In summary, while C 10 OOc 12 O was previously proposed to sensitize GNB to host plasma antibacterial proteins (29), the present study provides evidence for the MAC's capacity to perform much better in the presence of an antibiotic, bestowing potent antibacterial activity onto virtually inactive endogenous and/or exogenous compounds. In this sense, the current work ratifies the conclusions drawn in previous studies (20,28,29) that propose that the newly found antibacterial potencies are likely to stem from the damaged OM and/or CM, thereby supporting this approach's potential usefulness in the search of new alternatives to antibiotics.…”
Section: Enhancing In Vivo Efficacies Through Combination Therapiessupporting
confidence: 84%
“…However, data shown in Fig. 2B, as well as results from previous studies (18,28), argue against such a possibility. In fact, even less hydrophobic analogs (e.g., C 8 KKc 12 K) were able to damage the OM.…”
We recently reported the aptitude of a membrane-active lipopeptide (COOcO) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis-sepsis model for mono- and combination therapies. We found that by altering permeability of both outer and inner membranes, subinhibitory concentrations of COOcO can transiently sensitize GNB to diverse cytoplasm-targeting antibiotics in simple media. Sensitization was maintained in plasma, where COOcO instigated greater bactericidal activities, including in the presence of a bacteriostatic antibiotic (erythromycin). Single-dose administrations of rifampin and COOcO to -infected mice resulted in 55% 0, and 36% viability, respectively, for combined and individual treatments. Combining COOcO and erythromycin has similarly improved mice protection from developing fatal sepsis. Consequently, the data confirmed that COOcO renders GNB sensitive to both endogenous and exogenous antibacterials, and suggested that the tripartite concomitant presence increases therapeutic efficacy synergistically. This approach might expand the available treatment options to comprise antimicrobials with low permeability and/or efflux issues.-Jammal, J., Zaknoon, F., Mor, A. Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics.
“…3). Under similar conditions 46 the analogs C 8 , C 10 and C 12 exhibited a binding affinity that was lower than that of C 14 KKc 12 K but increased with increasing hydrophobicity 40 . This is further addressed below.Figure 3Dansyl-polymyxin binding assay.…”
Previous studies of the oligoacyllysyl (OAK) series acyl-lysyl-lysyl-aminoacyl-lysine-amide, suggested their utility towards generating robust linear lipopeptide-like alternatives to antibiotics, although to date, none exhibited potent broad-spectrum bactericidal activity. To follow up on this premise, we produced a new analog (C14KKc12K) and investigated its properties in various media. Mechanistic studies suggest that C14KKc12K uses a non-specific membrane-disruptive mode of action for rapidly reducing viability of Gram-negative bacteria (GNB) similarly to polymyxin B (PMB), a cyclic lipopeptide used as last resort antibiotic. Indeed, C14KKc12K displayed similar affinity for lipopolysaccharides and induced cell permeabilization associated with rapid massive membrane depolarization. Unlike PMB however, C14KKc12K was also bactericidal to Gram-positive bacteria (GPB) at or near the minimal inhibitory concentration (MIC), as assessed against a multispecies panel of >50 strains, displaying MIC50 at 3 and 6 µM, respectively for GPB and GNB. C14KKc12K retained activity in human saliva, reducing the viability of cultivable oral microflora by >99% within two minutes of exposure, albeit at higher concentrations, which, nonetheless, were similar to the commercial gold standard, chlorhexidine. This equipotent bactericidal activity was also observed in pre-formed biofilms of Streptococcus mutans, a major periodontal pathogen. Such compounds therefore, may be useful for eradication of challenging poly-microbial infections.
“…The synergism may result from complement proteins and/or clotting factors [60]. Further, a single combined dose of oligo-acyl-lysyls (OAKs) with rifampin also imparts increased survival chances from 10–20% to 60% against Klebsiella infected mice [61]. In addition, the combination of a lipopeptide bacillomycin D with antifungal amphotericin B leads to excellent antibiofilm and wound-healing properties against Candida albicans [62].…”
Section: Application Strategies Of Antimicrobial Peptidesmentioning
This review deals with the design and application strategies of new antibiotics based on naturally occurring antimicrobial peptides (AMPs). The initial candidate can be designed based on three-dimensional structure or selected from a library of peptides from natural or laboratory sources followed by optimization via structure-activity relationship studies. There are also advanced application strategies such as induction of AMP expression from host cells by various factors (e.g., metals, amino acids, vitamin D and sunlight), the use of engineered probiotic bacteria to deliver peptides, the design of prodrug and peptide conjugates to improve specific targeting. In addition, combined uses of newly developed AMPs with existing antimicrobial agents may provide a practical avenue for effective management of antibiotic-resistant bacteria (superbugs, including biofilm). Finally, we highlight AMPs already in use or under clinical trials.
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