12-Bis-THA Cl2 12,12′-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated ...for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.
C5-acylaminomethyl part of oxazolidinone antibiotics has a very restrictive Structure Activity Relationship (SAR). Only lipophilic and smaller substituents are tolerated at this position while polar ...and aromatic substitutions result in significant reduction in antimicrobial activity.
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Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.
A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against ...multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5–4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16–32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.
The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial ...biofilms is reported. Four carbonyl compounds of general formula fac-Mn(N∧N)(CO)3(L) have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435–450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay). The antibacterial activity of the four PhotoCORMs has been investigated against a panel of ESKAPE bacteria. The compounds 1–3 were found to be effective antibacterials at low concentrations against multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii when photoactivated with blue-light. In addition, the PhotoCORMs 1–2 were found to inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii bacterial biofilms at low concentrations (MIC = 4–8 μg/mL), turning out to be promising candidates to combat antimicrobial resistance. The antibacterial and biofilm inhibitory effect of the PhotoCORMs is plausibly due to the release of CO as well as the formation of phenanthroline photo-by-products as revealed by spectroscopy and microbiology experiments.
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•Phenanthroline-based manganese(I) PhotoCORMs were synthesized and found to possess antibacterial activity.•PhotoCORMs release carbon monoxide (CO) when irradiated with visible light (blue or green).•PhotoCORMs show antibacterial activity against Gram negative bacteria when irradiated with blue LED light.•PhotoCORMs inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii biofilms at low concentrations.•The release of CO and the formation of photo-by-products are responsible for the antibacterial and anti-biofilm activity.
Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse ...of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
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•Novel 1,5-diphenyl-pyrrole derivatives were synthesized.•The new compounds are endowed with high antibacterial activity.•The phenyl substituents at N1 and C5 of the pyrroles is essential for activity.•Protonatable guanidine/amino moieties improve the activity against Gram-ve bacteria.•Bacterial DNA gyrase was identified as a plausible target.
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A novel series of pyridyl nitrofuranyl isoxazolines were synthesized and evaluated for their antibacterial activity against multiple drug resistant (MDR) Staphylococcus strains. ...Compounds with piperazine linker between the pyridyl group and isoxazoline ring showed better activity when compared to compounds without the piperazine linker. 3-Pyridyl nitrofuranyl isoxazoline with a piperazine linker was found to be more active than corresponding 2-and 4-pyridyl analogues with MICs in the range of 4–32µg/mL against MDR Staphylococcus strains. The eukaryotic toxicity of the compounds was tested by MTT assay and were found to be non-toxic against both non-tumour lung fibroblast WI-38 and cervical cancer cell line HeLa. The most active pyridyl nitrofuranyl isoxazoline compound showed improved activity against a panel of Staphylococcus strains compared to nitrofuran group containing antibiotic nitrofurantoin.
Of the thousands of natural product antibiotics discovered to date, only a handful have been developed for the treatment of bacterial infection. The clinically unexploited majority likely include ...compounds with untapped potential as antibacterial drugs, and in view of the ever-growing unmet medical need for such agents, warrant systematic re-evaluation. Here we revisit the actinorhodins, a class that was first reported 70 years ago, but which remains poorly characterized. We show that γ-actinorhodin possesses many of the requisite properties of an antibacterial drug, displaying potent and selective bactericidal activity against key Gram-positive pathogens (including Staphylococcus aureus and enterococci), a mode of action distinct from that of other agents in clinical use, an extremely low potential for the development of resistance, and a degree of in vivo efficacy in an invertebrate model of infection. Our findings underscore the utility of revisiting unexploited antibiotics as a source of novel antibacterial drug candidates.
MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile ...associated disease. Its precise mechanism of action and the origin of limited activity against Gram-negative pathogens are relatively unknown. Herein, treatment with MGB-BP-3 alone significantly inhibited the bacterial growth of the Gram-positive, but not Gram-negative, bacteria as expected. Synergy assays revealed that inefficient intracellular accumulation, through both permeation and efflux, is the likely reason for lack of Gram-negative activity. MGB-BP-3 has strong interactions with its intracellular target, DNA, in both Gram-negative and Gram-positive bacteria, revealed through ultraviolet–visible (UV–vis) thermal melting and fluorescence intercalator displacement assays. MGB-BP-3 was confirmed to bind to dsDNA as a dimer using nano-electrospray ionization mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Type II bacterial topoisomerase inhibition assays revealed that MGB-BP-3 was able to interfere with the supercoiling action of gyrase and the relaxation and decatenation actions of topoisomerase IV of both Staphylococcus aureus and Escherichia coli. However, no evidence of stabilization of the cleavage complexes was observed, such as for fluoroquinolones, confirmed by a lack of induction of DSBs and the SOS response in E. coli reporter strains. These results highlight additional mechanisms of action of MGB-BP-3, including interference of the action of type II bacterial topoisomerases. While MGB-BP-3′s lack of Gram-negative activity was confirmed, and an understanding of this presented, the recognition that MGB-BP-3 can target DNA of Gram-negative organisms will enable further iterations of design to achieve a Gram-negative active S-MGB.
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