Antibiotic Resistance and Novel Therapeutic Strategies
Antimicrobial peptides (AMPs) are cationic, amphipathic peptides that are 15–30 amino acids in length, which are a part of the innate immune system of animals and plants in nature, but can also be produced by bacteria and fungi. AMPs can bind to negatively charged structural molecules on the microbial membrane with a broad spectrum of antimicrobial activity and reducing the likelihood of the bacteria developing resistance, and thus they potently act on slow- or non-growing bacteria, as observed in biofilms.
What drives bacteria to produce a biofilm?
Bacteria reap a number of benefits from the biofilm mode of growth and it is likely that different forces motivate bacteria to transition to one of a variety of biofilm states depending on the genetic makeup of the organism and its environment. It almost seems counter-intuitive that the biofilm mode of growth could confer a reproductive fitness advantage when one considers that biofilm bacteria have a reduced rate of growth relative to bacteria growing planktonically in broth culture. Outside of the laboratory, however, bacteria rarely, if ever, find themselves in an environment as nutrient rich as culture media, and in these less-than-ideal conditions, there are a number of fitness advantages imparted by the biofilm mode of growth.
The application of biofilm science to the study and control of chronic bacterial infections
Direct structural examination of biofilms showed that their component micro-colonies, which are composed of cells (±15% by volume) embedded in matrix material (±85% by volume), are bisected by ramifying water channels that carry bulk fluid into the community by convective flow. Direct measurement of several parameters by the use of microelectrodes established that biofilms are structurally and metabolically heterogeneous and that aerobic and anaerobic processes occur simultaneously in different parts of the multicellular community. Although antibiotic therapy and activated host defenses can kill derived planktonic cells and often obviate symptoms, they cannot kill the biofilm cells that constitute the niduses of these chronic infections.
Topographical and temporal diversity of the human skin microbiome
The effectiveness of antimicrobial agents in the management of some common skin disorders supports a role for microbes in pathophysiology. Elucidation of the baseline skin microbiome is a step toward testing the therapeutic potential of manipulating the microbiome in skin disorders. Indeed, an initial study of psoriasis and an animal model of ichthyosis describe selective microbial shifts associated with skin diseases. Targeted therapies to maintain healthy skin might require not only inhibiting the growth of pathogenic bacteria, but also promoting the growth of symbiotic bacteria.
Microbial biofilms and the human skin microbiome
Recent studies have established the link between the development of the resident immune system of the skin and the skin microbiota and have demonstrated a direct contact between the two. Several bacterial species isolated from human skin have demonstrated their ability to form biofilms both in vitro and in vivo. In their biofilm state, bacteria present differential metabolic and physiological functions often rendering them more virulent and resistant to antibiotics. In this state they may be involved in the etiology and exacerbation of skin disorders. Additionally, the role of quorum sensing, or bacterial cell–cell communication, a significant regulator of biofilm formation, has been expounded partially in relation to bacterial infections. Some limited evidence for the involvement of biofilms has been reported for additional skin disorders such as bullous impetigo, furuncle, and pemphigus foliaceus. Such reports further demonstrate that microorganisms can develop biofilms that are able to grow and persist on skin surfaces and appendages, necessitating further investigations.
Antimicrobial activity of metals: mechanisms, molecular targets and applications
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 effects of copper(II) bis(thiosemicarbazonato) complexes
Antimicrobial effects of copper(II) bis(thiosemicarbazonato) complexes provide new insight into their biochemical mode of action. We observed that Cu(btsc) interacted with proteins in the cell membrane. Systematic measurements of O2 uptake further demonstrated that treatment with both Cu(atsm) and Cu(gtsm) led to dose-dependent inhibition of respiratory electron transfer processes via succinate and NADH dehydrogenases. These dehydrogenases were not inhibited by a non-btsc source of Cu(II). The results led us to conclude that the biochemical mechanism of Cu(btsc) action is likely more complex than the present, simplistic model of copper release into the cytoplasm.
Copper homeostasis at the host-pathogen interface
Recent studies suggest that the macrophage phagosome accumulates copper during bacterial infection, which may constitute an important mechanism of killing. Bacterial countermeasures include the up-regulation of copper export and detoxification genes during infection, which studies suggest are important determinants of virulence. In this minireview, we summarize recent developments that suggest an emerging role for copper as an unexpected component in determining the outcome of host-pathogen interactions.
The antimicrobial and antibiofilm activities of copper(II) complexes
Biofilm-related bacterial infections pose a significant problem, as they are generally more tolerant to antibiotics and the immune system. Development of novel compounds with antibiofilm activity is therefore paramount. The antibiofilm activity was then determined against a clinical isolate of meticillin-resistant Staphylococcus aureus (MRSA). Strikingly, the copper complexes tested showed significant activity against biofilms, and were better in the removal of biofilms than vancomycin, an antibiotic that is currently used in the treatment of MRSA infections.
Zinc - role in immunity, oxidative stress and chronic inflammation
Zinc is essential for multiple cellular functions including immunity. Many investigators have used zinc supplementation in an attempt to affect the outcome of various diseases.In this review, recent findings of zinc supplementation in various diseases have been presented. Beneficial therapeutic response of zinc supplementation has been observed in the diarrhea of children, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory tract infection, common cold, and leishmaniasis. Zinc supplementation was effective in decreasing incidences of infections in the elderly, in patients with sickle cell disease (SCD) and decreasing incidences of respiratory tract infections in children. Zinc supplementation has prevented blindness in 25% of the elderly individuals with dry type of AMD. Zinc supplementation was effective in decreasing oxidative stress and generation of inflammatory cytokines such as TNF-alpha and IL-1beta in elderly individuals and patients with SCD.
Antibacterial Activity and Mechanism of Action of Zinc Oxide Nanoparticles against Campylobacter jejuni
In summary, ZnO nanoparticles exhibited remarkable antibacterial activity and demonstrated a lethal effect against C. jejuni, even at low concentrations. ZnO nanoparticles induced significant morphological changes, measurable membrane leakage, and substantial increases (up to 52-fold) in oxidative stress gene expression in C. jejuni. Based on these phenomena and cell responses, a plausible mechanism of ZnO inactivation of bacteria involves the direct interaction between ZnO nanoparticles and cell surfaces, which affects the permeability of membranes where nanoparticles enter and induce oxidative stress in bacterial cells, subsequently resulting in the inhibition of cell growth and eventually in cell death.
Zinc and immune function: the biological basis of altered resistance to infection
Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells.
Role of Zn2+ Ions in Host-Virus Interactions
The involvement of Zn2+ ions in the structure of ubiquitous protein zinc fingers gives this metal a particular position in the biology of the cell. Zinc has long been known as a trace element crucial for the proper folding and functioning of numerous proteins in the cell, including enzymes, signal transduction proteins, and transcription factors. However, deeper insights into the exact mechanistic role of zinc in different cellular processes, especially the physiological role of free-Zn2+ ions present in the cell, were limited, while the key elements of the cellular system regulating Zn2+ trafficking and storage remained unidentified.
Cu-doped zinc oxide and its polythiophene composites: preparation and antibacterial properties
Cu-doped zinc oxide and its polythiophene nanocomposites were prepared by the Sol–Gel and in situ polymerization methods, respectively. The structures, morphologies and compositions of the samples were characterized. The antibacterial properties of the samples on three kinds of strains were determined by using powder inhibition zones, minimum inhibitory concentrations and minimal bactericidal concentrations. The study confirmed that the antibacterial activities of the composites were better than those of their each component. The antibacterial mechanisms of the samples were discussed further.
Efficacy Of Copper To Reduce Acquisition Of Microbes and Healthcare-acquired Infections
Healthcare-acquired infections (HAI) cause substantial patient morbidity and mortality. Commonly touched items in the patient care environment harbor microorganisms that may contribute to HAI risk. Thus, reduction in the surface bioburden may be an effective strategy to reduce HAI. Inherent biocidal capabilities of copper surfaces offer a theoretical advantage to conventional cleaning, as disinfection is continuous rather than episodic.
β-Diketones as Scaffolds for Anticancer Drug Design – From Organic Building Blocks to Natural Products and Metallodrug Components
The β-diketone scaffold is a key intermediate in the synthesis of COX-2 inhibitors, a type of non-steroidal anti-inflammatory agents of the coxib family, which have also been shown to have excellent anticancer potential at the preclinical stage of research. Moreover, it is also present in the family of natural products named curcuminoids. Both natural products and their synthetic analogues possess interesting antibacterial, neuroprotective and anticancer properties. Coordination compounds of curcuminoids with platinum-group metals as potential anticancer agents are a hot topic of current research, with most scientific articles on this topic having been published in the last five years. Structurally simpler diketones, such as acetylacetone derivatives, are also employed in the design of new metal-based agents. Most notably, the first metal-based, non-platinum anticancer compound to enter clinical trials was budotitane – cis-diethoxy(1-phenylbutane-1,3-dionato)titanium(IV). Recently, several studies of platinum-group coordination and organometallic compounds, their biological evaluation and mode-of-action studies have been published in high-impact journals in the field of inorganic and medicinal chemistry.
Synthesis, Characterization, Antimicrobial and Antiproliferative Activity Evaluation of Cu(II), Zn(II), Co(II), Ni(II) and Pt(II) Complexes with Isoniazid-Derived Compound
The ligand and the metal complexes 1–8 have been screened for their in vitro antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Candida albicans strains and for their antiproliferative activity against MCF-7 and SKBR-3 human breast, A375 human melanoma, and NCI-H1573 lung adenocarcinoma cells. The quantitative antimicrobial activity test results proved that both the ligand and complex combinations have specific antimicrobial activity, depending on the microbial species tested. The biological property of these compounds can be explained on the basis of several factors involving type of donor atom present in ligands, the metal ion type and coordination geometry. In conclusion, our results may be useful in designing novel Cu(II) antimicrobial and
Zinc is an antioxidant and anti-inflammatory agent: its role in human health
Deficiency of zinc in humans was first reported nearly 50 years ago. The current estimate of the WHO is that nearly two billion subjects worldwide may have nutritional deficiency of zinc. This is because populations subsisting on high cereal protein diets have high intake of phytate, an organic phosphate compound, which complexes zinc and makes it unavailable for absorption. Major effects of zinc deficiency are growth retardation, hypogonadism, cell-mediated immune dysfunctions, increased oxidative stress, and increased generation of inflammatory cytokines. Zinc is a molecular signal for immune cells. Zinc is required for differentiation and generation of T helper cells. Generation of mRNA s of IL-2 and IFN-γ by Th1 cells are zinc-dependent and zinc-dependent transcription factors are involved in this process. Zinc supplementation to elderly subjects resulted in decreased incidences of infections, decreased plasma oxidative stress markers, and decreased generation of inflammatory cytokines and increased plasma zinc levels. Inasmuch as chronic inflammation and oxidative stress are implicated in many chronic diseases of the elderly, we hypothesize that zinc supplementation to the elderly may be very beneficial.
Randomized, Controlled Clinical Trial of Zinc Supplementation to Prevent Immunological Failure in HIV-Infected Adults
This study demonstrated that long-term (18-month) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time. This evidence supports the use of zinc supplementation as an adjunct therapy for HIV-infected adult cohorts with poor viral control.
A randomized clinical trial on the treatment of oral herpes with topical zinc oxide/glycine
Zinc oxide/glycine cream is an effective treatment for facial and circumoral herpes infection with predictable adverse effects that are completely reversible.
Using Copper to Improve the Well-Being of the Skin
Copper is an essential mineral that plays a key role in many physiological and metabolic processes, including angiogenesis, skin generation and expression and stabilization of extracellular skin proteins. Copper has also potent wide spectrum biocidal properties. The combination of these two distinct properties of copper makes copper a very attractive active material for the improvement of skin well-being. It is thus, not surprising that copper and copper compounds have been used by many different civilizations for more than 2 millennia to treat skin diseases, as well as other maladies.