An innovative new strategy to combat Staphylococcus aureus infections has been identified, according to a new study. The discovery could offer an important new direction for therapies to treat the bacterium, one which is becoming ever more resistant to antibiotics.
S. aureus, is a bacterium that flourishes on the skin and in the nose of one in three people. The bacterium is responsible for a wide range of both hospital- and community-acquired infections and, significantly, some strains have become extremely resistant to antibiotics. These drug-resistant strains, known as methicillin-resistant Staphylococcus aureus (MRSA), pose a serious public health threat; in the USA, MRSA is responsible for more deaths than HIV/AIDS.
In a study published back in 2005, George Liu and colleagues discovered that the pigment responsible for providing S. aureus with its yellow–orange color – ‘aureus’ is Latin for ‘golden’ – also provided the bacterium with a ‘golden armor’, protecting it from being killed by cells of the immune system.
The pigment is a carotenoid similar to β-carotene found in tomatoes and bright-colored vegetables such as carrots. It is thought that dietary carotenoids may have antioxidant properties, helping to protect human cells from harmful reactive oxygen molecules released by cells. Since neutrophils and macrophages utilize reactive oxygen molecules in order to kill invading bacteria, it was hyphothetized that staphyloxanthin was acting as an antioxidant, protecting S. aureus against the bacteriocidal chemicals produced by these cells. “We wondered if this carotenoid pigment could be protecting S. aureus from neutrophils and macrophages of the immune system,” said Liu, first author of the article.
By knocking out the gene in the pathway required to make staphyloxanthin, the team were able to strip S. aureus of its golden color, resulting in the creation of colorless bacteria. Importantly, these unpigmented bacteria had diminished virulence and were more susceptible to killing than wild-type bacteria.
Subsequently, Eric Oldfield, Professor of chemistry and biophysics at the University of Illinois (IL, USA), noticed that the biochemical pathway utilized to generate the staphyloxanthin pigment that has been knocked out in these bacteria had similarities, in its very early stages, to that which is required to make cholesterol in humans.
From this initial observation, it was then discovered that one of the S. aureus enzymes utilized in an early step of the pathway very closely resembled an enzyme required to make cholesterol in humans. Oldfield contacted the team behind the original ‘golden armor’ study, drawing their attention to the remarkable structural similarities between the two enzymes. He hypothesized that a drug designed to block the activity of the cholesterol-producing enzyme would also be able to bind to and interrupt the activity of the enzyme needed to produce staphyloxanthin. In this way, S. aureus could be stripped of its pigment, rendering it more susceptible to treatment or clearance by cells of the immune system.
Now, 3 years on from the publication of the original 2005 paper, an international team of researchers, including Liu and Oldfield, have blocked staphyloxanthin biosynthesis in vitro using a drug previously trialled for its cholesterol-lowering activity in humans.
In total, the team screened nine different drugs that act on the human cholesterol-producing enzyme. Of these, three drugs stripped the ability of S. aureus to synthesize staphyloxanthin, resulting in colorless bacteria.
One of the compounds tested, which has already progressed through two early clinical trials in humans as a cholesterol-lowering agent, was particularly effective; after treatment with the drug, the bacteria were approximately 15-fold more susceptible to killing by hydrogen peroxide and approximately fourfold less able to survive in human blood.
Moreover, the team were able to block S. aureus infections in mice using this compound; treating S. aureus-infected mice with the drug allowed for the in vivo clearance of bacteria by the innate immune system, reducing the bacterial population by 98%.
This discovery has disclosed a novel approach to treating S. aureus, which may have important clinical implications. It could offer a new direction for therapies against these potentially lethal infections, helping to reduce the burden of hospital-acquired infections on the healthcare system. Further research is now required to determine whether this strategy will translate into a clinical setting. “This is an entirely new approach that seems to work in animals, and now we need to take the next step to explore if it will work in humans.” said Oldfield.
Sources: Liu CI, Liu GY, Song Y et al. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319(5868), 1391–1394 (2008); Lui GY, Essex A, Buchanan JT et al.Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202(2), 209–215 (2005).
Catheter to combat bloodstream infections
Cook Medical Inc. (IN, USA) has announced the general availability in Europe of Cook Spectrum® Glide™ catheters – devices that have been specifically designed to provide heightened protection against catheter-related bloodstream infections (CRBSIs).
Healthcare-associated infections continue to receive a great deal of attention from the media, politicians, healthcare professionals and patients alike. Much of the negative press is fuelled by the fact that many of these infections are preventable; according to the UK’s National Audit Office, hospital-acquired infections across the NHS can be reduced by approximately 15% simply through better management and control.
Initiatives to tackle healthcare-associated infections and improve cleanliness are being put into practice across the healthcare system, with a key intervention being the implementation of proper hand hygiene protocols. Numerous other strategies are also being incorporated into infection-control procedures.
The development of the Spectrum Glide catheter is one example of a preventative strategy being implemented in the battle to reduce infection rates; representing a technological means of helping to circumvent CRBSIs. “The NHS as a whole is taking great strides to reduce hospital-acquired infections by adopting a variety of measures, including the adoption of innovative technology. The Cook Spectrum catheter is one such example of this technology,” says Duncan Wyncoll, Consultant Intensivist at St Thomas’s Hospital in London.
CRBSIs are one of the major healthcare-associated infections. Not only are they associated with considerable morbidity and mortality, the accompanying financial burden of treating such infections is also highly significant; according to the UK Department of Health, CR-BSIs cost the NHS in excess of £6209 per infected patient in 2003 alone. Since antibiotic therapy to treat the infections is so costly and is also associated with side effects, it is important to focus initiatives to tackle CRBSIs on prevention. “Efforts to beat CRBSIs must come from a platform of prevention, not just cure. This is precisely why we’ve designed the Spectrum Glide Catheter.” says Bruce Gingles of Cook Medical.
The catheters themselves are impregnated with a combination of the antibiotics rifampicin and monocycline, giveing broad-spectrum antibiotic activity against both Gram-positive and Gram-negative organisms and therefore providing enhanced protection against CRBSIs compared with catheters currently in use.
It is hoped that the usage of Spectrum Glide catheters will enhance patient safety and improve clinical outcomes, aiding in the ongoing effort to drive down CRBSI rates.
Source: Cook Medical Inc., IN, USA: www.cookmedical.com
New malaria drug may also be effective against toxoplasmosis
Prodrug: JPC-2056
Indication: Oral, antimalarial
A novel drug, scheduled to enter clinical trials for the treatment of malaria later in 2008, also appears to be effective against toxoplasmosis, according to new research. The drug holds considerable promise for the global treatment of toxoplasma infection.
Toxoplasmosis, a disease caused by the protozoan parasite Toxoplasma gondii, is a hugely significant parasitic infection in the world, with almost a third of the world’s population estimated to be infected.
During the first few weeks of infection, toxoplasmosis is typically asymptomatic or causes only mild influenza-like symptoms. After this initial period, it is rare for otherwise healthy adults to experience any other symptoms. However, the disease can cause considerable morbidity, occasionally even mortality, in those with weakened or immature immune systems. At-risk individuals therefore include immunocompromised cancer patients, HIV/AIDS sufferers, transplant recipients and fetuses.
Current medicines for toxoplasmosis are not well tolerated and can cause hypersensitivity reactions. Furthermore, there are no medications for certain latent stages of the parasite’s lifecycle and there is no vaccine available. New medications to combat the disease are, therefore, urgently required.
A team of researchers have recently demonstrated that a drug initially developed to treat malaria is also highly effective against T. gondii. The drug, known as JPC-2056, was rapidly effective both in tissue culture and in mice, significantly reducing the parasite burden within a matter of days.
T. gondii belongs to the same protozoan phylum as Plasmodium falciparum and Plasmodium vivax, the two parasites responsible for the most serious forms of human malaria. JPC-2056 works by inhibiting the action of an enzyme produced by this group of parasites, dihydrofolate reductase (DFHR). Although humans also have a version of DFHR, this is structurally distinct from the parasitic enzyme so the drug has much less effect on the human enzyme. As a result, this new class of medicine could be less toxic than currently available toxoplasmosis drugs. Significantly, the drug also appears to be ten-times more effective than pyrimethamine, the key medicine in the current gold-standard treatment for toxoplasmosis.
The results of this preliminary study suggest that JPC-2056 may have the potential to replace existing toxoplasmosis medications and could signify a major advance in the treatment of the disease.
Source: Mui EJ, Schiehser GA, Milhous WK et al. Novel triazine JPC-2067-B inhibits Toxoplasma gondiiin vitro and in vivo. PLoS Negl. Trop. Dis. 2(3), e190 (2008).
Infectious blindness could be reduced by twice-annual antibiotic therapy
Children receiving antibiotic therapy twice per year instead of just once per year are at a significantly reduced risk of contracting potentially blinding contagious eye infections, according to a recent study.
The results of this new research suggest that, through the implementation of proper antibiotic programs, a considerable amount of third-world blindness could be avoided.
Trachoma, a contagious eye infection caused by the bacterium Chlamydia trachomatis, is the leading cause of the world’s preventable blindness. Although trachoma was eliminated from much of the developed world in the last century, the disease persists in many parts of the developing world.
The results of a 2-year study into the effect of the frequency of antibiotic therapy on reducing trachoma infection were published recently. Researchers analyzed infection levels from 16 rural villages in Ethiopia with a high prevalence of trachoma, comparing infection levels between residents of villages receiving one dose of the antibiotic azithromycin per year and residents of villages receiving two doses per year.
Trachoma infection levels were significantly reduced in those villages whose residents received azithromycin biannually. In some villages, there was a sixfold decrease in infections of preschool children who received two annual treatments compared with one. Furthermore, 75% of biannually treated preschool children were infection free at the end of the study compared with just 12.5% of children receiving one dose.
These findings suggest that biannual antibiotic coverage could be the best way forward in order to reduce trachoma infection in developing countries. “Although programmes may be reluctant to devote their scarce resources to more frequent treatment, this may be more cost effective in the long term.” say the researchers.
However, there are fears that mass antibiotic administration may result in the emergence of antibiotic resistance. Authors of a recent topical editorial offer some words of caution. “Studies to examine whether more frequent azithromycin use will result in the emergence of macrolide-resistant strains of C. trachomatis or other important pathogens are urgently required.”
Despite such concerns, the results of this study represent a significant step forward in our understanding of what is required to effectively reduce blinding trachoma infections in the developing world.
Sources: Melese M, Alemayehu W, Lakew T et al. Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma. JAMA 299 (7), 778–784 (2008); Mabey D, Solomon AW. Mass antibiotic administration for eradication of ocular Chlamydia trachomatis. JAMA 299 (7), 819–820 (2008).
Many maternal deaths may be preventable
A large proportion of women who die during pregnancy and in childbirth in sub-Saharan Africa do so from treatable infectious diseases rather than from causes directly linked to pregnancy, according to a new study.
This novel finding suggests that, through the implementation of treatment strategies to combat certain infectious diseases, the global maternal death toll could be reduced dramatically.
Although there are only eight maternal deaths per 100,000 live births in the developed world, maternal mortality remains a significant problem in poorer parts of the world; in sub-Saharan Africa, the rate is a staggering 1000 deaths per 100,000 live births and the region itself accounts for half of all global maternal deaths.
In a recently published study, autopsies were performed on 139 pregnant women in Mozambique, a country located in sub-Saharan Africa. The study, carried out over a period of 2 years, yielded unexpected results.
Previously, it had been assumed that the primary cause of maternal deaths in the developing world were obstetric complaints – conditions that are a direct result of pregnancy and giving birth. However, the researchers found that such conditions only accounted for 38% of deaths. By contrast, infectious diseases not specifically linked to pregnancy or delivery accounted for 48% of the deaths. Important causes of death were HIV/AIDS-related conditions, malaria and bacterial infections leading to meningitis and pneumonia.
This unforeseen discovery – that infectious diseases not related to pregnancy account for more maternal deaths in the developing world than do obstetric complications – may have significant implications as regards where to concentrate resources and how best to develop effective health policies in order to reduce maternal mortality rates. The findings of this study indicate that effective prevention and treatment strategies to combat certain infectious diseases may be an effective method of dramatically reducing the number of maternal deaths worldwide.
Source: Menendez C, Romagosa C, Ismail MR et al. An autopsy study of maternal mortality in Mozambique: The contribution of infectious diseases. PLoS Med. 5(2), e44 (2008).