Two new epimeric bibenzylated monoterpenes machaerifurogerol (
) and 5-
-machaerifurogerol (
), and four known isoflavonoids (+)-vestitol (
), 7-
-methylvestitol (
), (+)-medicarpin (
), and ...3,8-dihydroxy-9-methoxypterocarpan (
) were isolated from
Pers. This plant was previously assigned as
Spruce, from which machaeriols A-D (
-
) and machaeridiols A-C (
-
) were reported, and all were then re-isolated, except the minor compound
, for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture
+
was the most active with an MIC value of 1.25 μg/mL against methicillin-resistant
(MRSA) strains BAA 1696, -1708, -1717, -33591, and vancomycin-resistant
(VRE 700221) and
.
(VRE 51299) and vancomycin-sensitive
(VSE 29212). Compounds
-
and
-
were found to be more potent against MRSA 1708, and
,
, and
against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriols (
or
) and machaeridiols (
or
), which exhibited a strong synergistic activity of
+
(MIC 0.156 and 0.625 µg/mL), with >32- and >8-fold reduction of MIC's, compared to
, against MRSA 1708 and -1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds
+
,
,
, and
showed activity in the range of 0.5-8 µg/mL for two strains of
, 2-16 µg/mL against
PAO1, and 2 µg/mL against
NCTC 12923, but were inactive (MIC > 64 µg/mL) against the two isolates of
.
Invasive Candida infections in hospitalized and immunocompromised or critically ill patients have become an important cause of morbidity and mortality. There are increasing reports of multidrug ...resistance in several Candida species that cause Candidemia, including C. glabrata and C. auris, with limited numbers of antifungal agents available to treat patients with invasive Candida infections. Therefore, there is an urgent need to discover new antifungal agents that work against multidrug‐resistant Candida species, particularly C. auris, which has been identified as an emerging global pathogen. In this article, we report a new class of antifungal agents, the Schiff bases of sulphonamides, that show activity against all Candida species tested, with an MIC range of 4–32 µg/ml. Compound 2b showed activity against C. glabrata and a panel of fluconazole‐resistant C. auris strains, with MICs of 4–16 µg/ml. The drug‐like nature of these Schiff bases offers opportunities to optimize these compounds with medicinal chemistry techniques to obtain more potent analogs that can be progressed toward pre‐clinical evaluation.
We report a new class of antifungal agents, the Schiff bases of sulphonamides, that show activity against all Candida species tested including multidrug‐resistant C. auris. The drug‐like nature of these Schiff bases offers opportunities to optimize these compounds with medicinal chemistry techniques to obtain more potent analogs that can be progressed toward pre‐clinical evaluation.
Antimicrobial resistance has increased rapidly, causing daunting morbidity and mortality rates worldwide. Antimicrobial peptides (AMPs) have emerged as promising alternatives to traditional ...antibiotics due to their broad range of targets and low tendency to elicit resistance. However, potent antimicrobial activity is often accompanied by excessive cytotoxicity toward host cells, leading to a halt in AMP therapeutic development. Here, we present multivariate analyses that correlate 28 peptide properties to the activity and toxicity of 46 diverse African-derived AMPs and identify the negative lipophilicity of polar residues as an essential physiochemical property for selective antimicrobial activity. Twenty-seven active AMPs are identified, of which the majority are of scorpion or frog origin. Of these, thirteen are novel with no previously reported activities. Principal component analysis and quantitative structure–activity relationships (QSAR) reveal that overall hydrophobicity, lipophilicity, and residue side chain surface area affect the antimicrobial and cytotoxic activity of an AMP. This has been well documented previously, but the present QSAR analysis additionally reveals that a decrease in the lipophilicity, contributed by those amino acids classified as polar, confers selectivity for a peptide to pathogen over mammalian cells. Furthermore, an increase in overall peptide charge aids selectivity toward Gram-negative bacteria and fungi, while selectivity toward Gram-positive bacteria is obtained through an increased number of small lipophilic residues. Finally, a conservative increase in peptide size in terms of sequence length and molecular weight also contributes to improved activity without affecting toxicity. Our findings suggest a novel approach for the rational design or modification of existing AMPs to increase pathogen selectivity and enhance therapeutic potential.
The
fluoroquinolone class of antibiotics has a well-established
structure–activity relationship (SAR) and a long history in
the clinic, but the effect of electron-rich benzofused substituents
at the ...N1 position remains poorly explored. Because groups at this
position are part of the topoisomerase–DNA binding complex
and form a hydrophobic interaction with the major groove of DNA, it
was hypothesized that an electron-rich benzofused N1 substituent could
enhance this interaction. Molecular modeling techniques were employed
to evaluate the binding of certain N1-modified fluoroquinolones to
DNA gyrase targets from both
Staphylococcus aureus
and
Klebsiella pneumoniae
species
compared with ciprofloxacin and norfloxacin. Seven N1-modified fluoroquinolones
were subsequently synthesized and tested against a panel of Gram-negative
pathogens to determine minimum inhibitory concentration (MIC) values.
Gram-negative outer membrane penetration was investigated using the
membrane permeabilizer polymyxin B nonapeptide and compound efflux
via
resistance–nodulation–division-family
efflux transporters was evaluated using the known efflux pump inhibitor
phenylalanine–arginine β-naphthylamide. Additionally,
the target inhibitory activity of representative compound
6e
was determined in a cell-free environment. A correlation between
N1 substituent hydrophobicity and activity was observed across the
MIC panel, with compound activity decreasing with increased hydrophobicity.
Those compounds with highest hydrophobicity were inactive because
of poor solubility profiles whereas compounds with intermediate hydrophobicity
were inactive because of impaired outer membrane penetration, and
reduced inhibition of topoisomerase targets, the latter in contrast
to modeling predictions. This study adds new information to the fluoroquinolone
SAR and suggests limited utility of large hydrophobic substituents
at the N1 position of fluoroquinolones.
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.
The pharmacodynamic profile of antimicrobial peptides (AMPs) and their in vivo synergy are two factors that are thought to restrict resistance evolution and ensure their conservation. The frog Rana ...temporaria secretes a family of closely related AMPs, temporins A–L, as an effective chemical dermal defense. The antibacterial potency of temporin L has been shown to increase synergistically in combination with both temporins B and A, but this is modest. Here we show that the less potent temporin B enhances the cooperativity of the in vitro antibacterial activity of the more potent temporin L against EMRSA-15 and that this may be associated with an altered interaction with the bacterial plasma membrane, a feature critical for the antibacterial activity of most AMPs. Addition of buforin II, a histone H2A fragment, can further increase the cooperativity. Molecular dynamics simulations indicate temporins B and L readily form hetero-oligomers in models of Gram-positive bacterial plasma membranes. Patch-clamp studies show transmembrane ion conductance is triggered with lower amounts of both peptides and more quickly when used in combination, but conductance is of a lower amplitude and pores are smaller. Temporin B may therefore act by forming temporin L/B hetero-oligomers that are more effective than temporin L homo-oligomers at bacterial killing and/or by reducing the probability of the latter forming until a threshold concentration is reached. Exploration of the mechanism of synergy between AMPs isolated from the same organism may therefore yield antibiotic combinations with advantageous pharmacodynamic properties.
The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the ...screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, and gemcitabine), anthracyclines (daunorubicin, mitoxantrone, and epirubicin), and psychoactive drugs (gabapentin, fluspirilene, and oxethazaine). These findings suggest that there are few approved drugs that could be directly repositioned as adjunct antibacterials, and these will need robust testing to validate efficacy.
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