11 research outputs found
Membrane Active Phenylalanine Conjugated Lipophilic Norspermidine Derivatives with Selective Antibacterial Activity
Natural and synthetic membrane active
antibacterial agents offer
hope as potential solutions to the problem of bacterial resistance
as the membrane-active nature imparts low propensity for the development
of resistance. In this report norspermidine based antibacterial molecules
were developed that displayed excellent antibacterial activity against
various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant
bacteria (methicillin-resistant <i>Staphylococcus aureus</i>, vancomycin-resistant <i>Enterococcus faecium</i>, and
β-lactam-resistant <i>Klebsiella pneumoniae</i>).
In a novel structure–activity relationship study it has been
shown how incorporation of an aromatic amino acid drastically improves
selective antibacterial activity. Additionally, the effect of stereochemistry
on activity, toxicity, and plasma stability has also been studied.
These rapidly bactericidal, membrane active antibacterial compounds
do not trigger development of resistance in bacteria and hence bear
immense potential as therapeutic agents to tackle multidrug resistant
bacterial infections
Structure–Activity Relationship of Amino Acid Tunable Lipidated Norspermidine Conjugates: Disrupting Biofilms with Potent Activity against Bacterial Persisters
The emergence of bacterial resistance
and biofilm associated infections
has created a challenging situation in global health. In this present
state of affairs where conventional antibiotics are falling short
of being able to provide a solution to these problems, development
of novel antibacterial compounds possessing the twin prowess of antibacterial
and antibiofilm efficacy is imperative. Herein, we report a library
of amino acid tunable lipidated norspermidine conjugates that were
prepared by conjugating both amino acids and fatty acids with the
amine functionalities of norspermidine through amide bond formation.
These lipidated conjugates displayed potent antibacterial activity
against various planktonic Gram-positive and Gram-negative bacteria
including drug-resistant superbugs such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and β-lactam-resistant Klebsiella pneumoniae. This class of nontoxic and
fast-acting antibacterial molecules (capable of killing bacteria within
15 min) did not allow bacteria to develop resistance against them
after several passages. Most importantly, an optimized compound in
the series was also capable of killing metabolically inactive persisters
and stationary phase bacteria. Additionally, this compound was capable
of disrupting the preformed biofilms of S. aureus and E. coli. Therefore, this class
of antibacterial conjugates have potential in tackling the challenging
situation posed by both bacterial resistance as well as drug tolerance
due to biofilm formation
A Biodegradable Polycationic Paint that Kills Bacteria <i>in Vitro</i> and <i>in Vivo</i>
Bacterial
colonization and subsequent formation of biofilms onto surfaces of
medical devices and implants is a major source of nosocomial infections.
Most antibacterial coatings to combat infections are either metal-based
or nondegradable-polymer-based and hence limited by their nondegradability
and unpredictable toxicity. Moreover, to combat infections effectively,
the coatings are required to display simultaneous antibacterial and
antibiofilm activity. Herein we report biocompatible and biodegradable
coatings based on organo-soluble quaternary chitin polymers which
were immobilized noncovalently onto surfaces as bactericidal paint.
The polycationic paint was found to be active against both drug-sensitive
and -resistant bacteria such as methicillin-resistant <i>Staphylococcus
aureus</i> (MRSA), vancomycin-resistant <i>Enterococcus
faecium</i> (VRE), and β-lactam-resistant <i>Klebsiella
pneumoniae</i>. The cationic polymers were shown to interact
with the negatively charged bacterial cell membrane and disrupt the
membrane integrity, thereby causing leakage of intracellular constituents
and cell death upon contact. Importantly, surfaces coated with the
polymers inhibited formation of biofilms against both Gram-positive <i>S. aureus</i> and Gram-negative <i>E. coli</i>, two
of the most clinically important bacteria that form biofilms. Surfaces
coated with the polymers displayed negligible toxicity against human
erythrocytes and embryo kidney cells. Notably, the polymers were shown
to be susceptible toward lysozyme. Furthermore, subcutaneous implantation
of polymer discs in rats led to 15–20% degradation in 4 weeks
thereby displaying their biodegradability. In a murine model of subcutaneous
infection, polymer-coated medical-grade catheter reduced MRSA burden
by 3.7 log compared to that of noncoated catheter. Furthermore, no
biofilm development was observed on the coated catheters under <i>in vivo</i> conditions. The polycationic materials thus developed
herein represent a novel class of safe and effective coating agents
for the prevention of device-associated infections
Antibacterial activity of NCK-10 at different physiological conditions.
<p>Antibacterial activity of NCK-10 at different physiological conditions.</p
Ability of NCK-10 to disrupt methicillin resistant <i>S</i>. <i>aureus</i> biofilms.
<p>(A) Reduction in viable bacterial count with respect to control at different concentrations of NCK-10. (B) Reduction in biofilm mass by crystal violet staining (Concentration of NCK-10 was 10×MIC). (C) Confocal of image of untreated biofilm and after treatment with NCK-10 (Concentration of NCK-10 was 10×MIC).</p
Small Molecular Antibacterial Peptoid Mimics: The Simpler the Better!
The emergence of multidrug resistant
bacteria compounded by the
depleting arsenal of antibiotics has accelerated efforts toward development
of antibiotics with novel mechanisms of action. In this report, we
present a series of small molecular antibacterial peptoid mimics which
exhibit high in vitro potency against a variety of Gram-positive and
Gram-negative bacteria, including drug-resistant species such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. The highlight of these compounds
is their superior activity against the major nosocomial pathogen Pseudomonas aeruginosa. Nontoxic toward mammalian
cells, these rapidly bactericidal compounds primarily act by permeabilization
and depolarization of bacterial membrane. Synthetically simple and
selectively antibacterial, these compounds can be developed into a
newer class of therapeutic agents against multidrug resistant bacterial
species
Aryl-alkyl-lysines: Membrane-Active Small Molecules Active against Murine Model of Burn Infection
Infections caused by drug-resistant
Gram-negative pathogens continue to be significant contributors to
human morbidity. The recent advent of New Delhi metallo-β-lactamase-1
(<i>bla</i>NDM-1) producing pathogens, against which few
drugs remain active, has aggravated the problem even further. This
paper shows that aryl-alkyl-lysines, membrane-active small molecules,
are effective in treating infections caused by Gram-negative pathogens.
One of the compounds of the study was effective in killing planktonic
cells as well as dispersing biofilms of Gram-negative pathogens. The
compound was extremely effective in disrupting preformed biofilms
and did not select resistant bacteria in multiple passages. The compound
retained activity in different physiological conditions and did not
induce any toxic effect in female Balb/c mice until concentrations
of 17.5 mg/kg. In a murine model of Acinetobacter baumannii burn infection, the compound was able to bring the bacterial burden
down significantly upon topical application for 7 days
Skin histopathology studies.
<p>(A) Untreated (B) Treated with Fusidic acid and (C) Treated with NCK-10.</p
Structures of the compounds used in the study.
<p>Structures of the compounds used in the study.</p
Kinetics of killing of <i>S</i>. <i>aureus</i> persister cells by NCK-10 at 5 × MIC.
<p>(*) indicate that no colony was observed.</p