Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, we describe the chemical and toxicological principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only our understanding of metal toxicity but also the design of metal-based compounds for use as antimicrobial agents and alternatives to antibiotics.

Antimicrobial activity of metals: mechanisms, molecular targets and applications

Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome, although they can also be plasmid-encoded. A previous article in this journal provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past 5 years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

Efflux-Mediated Drug Resistance in Bacteria

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Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?

F. Vinyl Sulfones and Other Michael Acceptors 4683 G. Azodicarboxamides 4695 IV. Acylating Agents 4695 A. Aza-peptides 4695 B. Carbamates 4699 C. Peptidyl Acyl Hydroxamates 4700 D. â-Lactams and Related Inhibitors 4704 E. Heterocyclic Inhibitors 4714 1. Isocoumarins 4715 2. Benzoxazinones 4722 3. Saccharins 4725 4. Miscellaneous Heterocyclic Inhibitors 4728 V. Phosphonylation Agents 4728 A. Peptide Phosphonates 4728 B. Phosphonyl Fluorides 4734 VI. Sulfonylating Agents 4735 A. Sulfonyl Fluorides 4735 VII. Miscellaneous Inhibitors 4736 VIII. Summary and Perspectives 4737 IX. Acknowledgments 4740 X. Note Added in Proof 4740 XI. References 4740

Irreversible inhibitors of serine, cysteine, and threonine proteases.

Efflux-mediated drug resistance in bacteria: an update.

Hydrogen peroxide is extensively used as a biocide, particularly in applications where its decomposition into
non-toxic by-products is important. Although increasing information on the biocidal efﬁcacy of hydrogen peroxide is available, there is still little understanding of its biocidal mechanisms of action. This review aims to
combine past and novel evidence of interactions between hydrogen peroxide and the microbial cell and its
components, while reﬂecting on alternative applications that make use of gaseous hydrogen peroxide. It is currently believed that the Fenton reaction leading to the production of free hydroxyl radicals is the basis of hydrogen peroxide action and evidence exists for this reaction leading to oxidation of DNA, proteins and membrane
lipids in vivo. Investigations of DNA oxidation suggest that the oxidizing radical is the ferryl radical formed from
DNA-associated iron, not hydroxyl. Investigations of protein oxidation suggest that selective oxidation of certain
proteins might occur, and that vapour-phase hydrogen peroxide is a more potent oxidizer of protein than liquidphase hydrogen peroxide. Few studies have investigated membrane damage by hydrogen peroxide, though it is
suggested that this is important for the biocidal mechanism. No studies have investigated damage to microbial
cell components under conditions commonly used for sterilization. Despite extensive studies of hydrogen peroxide toxicity, the mechanism of its action as a biocide requires further investigation.

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Use of hydrogen peroxide as a biocide: new consideration of its mechanisms of biocidal action

Objectives; Antimicrobials such as chlorine dioxide, peracetic acid and hydrogen peroxide (H2O2) share a basic mechanism of action (chemical oxidation of cellular components), but profound differences arise in their efficacy against microorganisms. Optimization of activity requires an understanding of their interaction with microbial targets and a clear differentiation between the chemical efficacies of each oxidative biocide. This study aimed to elucidate the biochemical mechanisms of action of oxidizing biocides at a macromolecular level, using amino acids, protein and an enzyme as model substrates for the action of each biocide.
Methods: The interactions of a number of oxidising agents (liquid and gaseous H2O2, ClO2, peracetic acid formulations) with amino acids, proteins (bovine serum albumin and aldolase) and enzymes were investigated by spectrophotometry, SDS-PAGE and alkaline phosphatase activity measurements.
Results: Biocide reactions yielded different types of oxidative structural change and different degrees of oxidation to amino acids and proteins, and differences in activity against a microbial enzyme. In particular there was a marked difference in the interactions of liquid H2O2 and gaseous H2O2 with the macromolecules, the latter causing greater oxidation; these results explain the dramatic differences in antimicrobial efficacy between liquid and gas peroxide.
Conclusions: These results provide a comprehensive understanding of the differences in interactions between a number of oxidizing agents and macromolecules commonly found in microbial cells. Biochemical mechanistic differences between these oxidative biocides do exist and lead to differential effects on macromolecules. This in turn could provide an explanation as to their differences in biocidal activity, particularly between liquid and gas peroxide.

Mode of action of hydrogen peroxide and other oxidizing agents: differences between liquid and gas forms

The study and synthesis of C-nucleosides has been extensive owing to their biological activity and potential as drug candidates for antiviral and anticancer therapy. Numerous synthetic strategies have also been investigated in order to optimize yields and stereoselectivity in the glycosylation reaction. Here we review one class of synthetic methods, direct condensation of a pre-formed aglycon unit with an appropriate sugar component.

Synthetic methodologies for C-nucleosides

Enzyme Classes and Mechanisms. Regulatory Mechanisms for Proteinase Activity. Matrix Metalloproteinases (MMPs). Proteasomes. Cathepsins. Calpain. Human Neutrophil Elastase Inhibitors. Thrombin. Inhibitors of Factor VIIa, Factor IXa, and Factor Xa as Anticoagulants. The Urokinase-Type Plasminogen Activator (uPA) System: A New Target for Tumor Therapy. Proteinases Involved in Amyloid ss-Peptide (Ass) Production and Clearance. Herpes Virus and Cytomegalovirus Proteinase. Human Rhinovirus 3C Proteinase Inhibitors. Aminopeptidases. The Hepatitis C Virus NS3 Serine-Type Proteinase. Zinc Metallopeptidases. HIV Aspartate Proteinase: Resistance to Inhibitors. Proteases of Protozoan Parasites for Proteinase Activity.

Proteinase and Peptidase Inhibition: Recent Potential Targets for Drug Development

The synthesis of a series of novel 1-[(benzofuran-2-yl)phenylmethyl]-pyridine, -imidazole, and -triazole derivatives is described. All the compounds were evaluated in vitro for inhibitory activity against aromatase (P450AROM, CYP19), using human placental microsomes. The 6-methoxy- and 6-hydroxy-substituted benzofuran derivatives were shown to be potent CYP19 inhibitors (IC50 = 0.01−1.46 μM) with activity greater than that observed for the unsubstituted parent compounds and inhibitory activity comparable with or greater than the reference compound arimidex (IC50 = 0.6 μM). Six of the benzofuran derivatives were subjected to in vitro cytotoxicity assays, using rat liver hepatocytes with cytotoxicity determined from alteration in cell morphology and lactate dehydrogenase enzyme retention over a period of 24 h, and selectivity (CYP17, 17β-HSD types 1 and 3, CYP24, and CYP26) determination; negligible inhibitory activity was observed, suggesting a good selectivity for CYP19. The pyridine benzofuran 4a containing the 4-fluorophenyl group was the most promising (IC50 = 44 nM; LC50 >100 μM) compared with arimidex (IC50 = 600 nM; LC50 > 200 μM).

Claire Simons

Papers

Use of hydrogen peroxide as a biocide: new consideration of its mechanisms of biocidal action

Mode of action of hydrogen peroxide and other oxidizing agents: differences between liquid and gas forms

Synthetic methodologies for C-nucleosides

Proteinase and Peptidase Inhibition: Recent Potential Targets for Drug Development

Potent CYP19 (aromatase) 1-[(benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole inhibitors: synthesis and biological evaluation.