Drug discovery: Leaving no stone unturned

Gammon, Katharine

doi:10.1038/509s10a

Cited by 20 publications

(14 citation statements)

References 8 publications

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“…The widespread emergence of multidrug-resistant (MDR) bacterial infections has led to increased interest in the search for new antibiotics (Gammon, 2014). Antimicrobial peptides (AMPs) are considered as potential alternatives to conventional antibiotics, as they possess broad-spectrum activity and distinct modes of action that are based on their compositional and structural diversity (Jenssen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

O'Brien-Simpson

Tailhades

et al. 2015

Chemistry & Biology

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A3-APO, a de novo designed branched dimeric proline-rich antimicrobial peptide (PrAMP), is highly effective against a variety of in vivo bacterial infections. We undertook a selective examination of the mechanism for the Gram-negative Escherichia coli bacterial membrane interaction of the monomer (Chex-Arg20), dimer (A3-APO), and tetramer (A3-APO disulfide-linked dimer). All three synthetic peptides were effective at killing E. coli. However, the tetramer was 30-fold more membrane disruptive than the dimer while the monomer showed no membrane activity. Using flow cytometry and high-resolution fluorescent microscopy, it was observed that dimerization and tetramerization of the Chex-Arg20 monomer led to an alteration in the mechanism of action from non-lytic/membrane hyperpolarization to membrane disruption/depolarization. Our findings show that the membrane interaction and permeability of Chex-Arg20 was altered by multimerization.

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Section: Introductionmentioning

confidence: 99%

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

O'Brien-Simpson

Tailhades

et al. 2015

Chemistry & Biology

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“…The widespread feeding of livestock with various antibiotics to aid their growth has also contributed to the enhancement of antibiotic resistance genes (Cully 2014;Zhu et al 2013). Consequently, much research is ongoing to investigate the mechanism of antibiotic resistance and seeks to develop new antibiotics possessing various mechanisms of action (Cannon 2014;Gammon 2014).…”

mentioning

confidence: 99%

Proline-rich antimicrobial peptides: potential therapeutics against antibiotic-resistant bacteria

et al. 2014

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The increasing resistance of pathogens to antibiotics causes a huge clinical burden that places great demands on academic researchers and the pharmaceutical industry for resolution. Antimicrobial peptides, part of native host defense, have emerged as novel potential antibiotic alternatives. Among the different classes of antimicrobial peptides, proline-rich antimicrobial peptides, predominantly sourced from insects, have been extensively investigated to study their specific modes of action. In this review, we focus on recent developments in these peptides. They show a variety of modes of actions, including mechanism shift at high concentration, non-lytic mechanisms, as well as possessing different intracellular targets and lipopolysaccharide binding activity. Furthermore, proline-rich antimicrobial peptides display the ability to not only modulate the immune system via cytokine activity or angiogenesis but also possess properties of penetrating cell membranes and crossing the blood brain barrier suggesting a role as potential novel carriers. Ongoing studies of these peptides will likely lead to the development of more potent antimicrobial peptides that may serve as important additions to the armoury of agents against bacterial infection and drug delivery.

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“…It is not simply that our interrogation now includes both terrestrial and marine organisms (Gerwick and Moore 2012;Gammon 2014) but, additionally, the recognition that our anthropomorphic interest in antibiotics belies the vastly more complex roles these structures have for communication within their ecological niches (Davies 2013). A direct implication from this understanding that the coculture of organisms can profoundly alter secondary metabolite expression is proven (Bertrand et al 2013;Rateb et al 2013;Kalghatgi et al 2013;Hopwood 2013).…”

Section: New Natural Products As Antibacterialsmentioning

confidence: 93%

“…While it is uncertain whether an event short of a pandemic will realize this sea change, the scientific and medical objectives for preserving successful antibacterial chemotherapy in the face of a seeming universe of resistance mechanisms are obvious. These objectives include the discovery of new antibacterials (Gammon 2014), the reincarnation of old antibacterials, the optimization of multi-agent chemotherapy by mechanistic correlation of interdependent targets, a better understanding of the control mechanisms for the expression of resistance mechanisms, a better understanding of the bactericidal mechanisms used by clinically successful antibacterials, and improved clinical trial design (Shlaes and Spellberg 2012;Dalhoff et al 2014). The exploitation of these discoveries, combined with a recognition of the importance of the clinical practices that ensure antibacterial efficacy (Bogan and Marchaim 2013;Ciccolini et al 2013), can preserve the antibiotic miracle (Bartlett et al 2013;Davies et al 2013).…”

Section: Introductionmentioning

confidence: 97%

Strategies for Circumventing Bacterial Resistance Mechanisms

Fisher

Johnson

Mobashery

2014

Handbook of Antimicrobial Resistance

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The future practices for the control of bacterial infections are uncertain. The intransigent infection is no longer found just among the immune compromised but is now found both in and out the boundaries of the hospital. Preserving the efficacy of the antibacterials we have, in order to secure the time needed to discover and develop new antibacterials, will require abrupt change: in the way antibacterials are dispensed and disposed, in the criteria used to measure clinical safety and efficacy, in the financial incentives for antibacterial development, and in the understanding of the molecular mechanisms governing the relationship between the antibacterial and the bacterium. This review examines this relationship from the particular perspective of the eventual need to circumvent resistance mechanisms in order to reclaim the lifesaving value of the antibacterial chemical.

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Drug discovery: Leaving no stone unturned

Cited by 20 publications

References 8 publications

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Proline-rich antimicrobial peptides: potential therapeutics against antibiotic-resistant bacteria

Strategies for Circumventing Bacterial Resistance Mechanisms

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