Tag: antibiotics (page 4 of 4)

more about bacteria

Gut bacteria and the microbiome seem to be a hot topic this month (see previous post on “the power of the gut“). Ed Yong discusses different enterotypes at  Nature News:

Each of us has trillions of bacteria in our guts. These communities vary greatly between individuals, but a paper published in Nature last year1 indicated that they fall into just three distinct types — enterotypes — defined by their bacterial composition (see ‘Gut study divides people into three types’). Each enterotype is characterized by relatively high levels of a single microbial genus: Bacteroides, Prevotella, or Ruminococcus, respectively.

But new data presented at the International Human Microbiome Congress in Paris yesterday suggest that the boundaries between the enterotypes may be fuzzier than the earlier work suggested.

The results, as yet unpublished, show that a genus of archaea called Methanobrevibacter joins Ruminococcus as a defining microbe in the third enterotype. And the separation between this cluster and the Bacteroides-led enterotype is no longer as clear, although these two groups remain distinct from the Prevotella-driven one.

More here. Meanwhile, at The Scientist, Kieran O’Doherty ponders the ethical implications of antibiotics and microbiome engineering as gut bacteria are such an integral part of our existence:

The issue of how stable an individual’s microbiome is over time also raises other ethical questions. For example, because human DNA is a unique identifier of individuals, there are many safeguards for ensuring the confidentiality of genetic data. In many jurisdictions laws have been enacted to prohibit insurance companies from taking the results of genetic tests into account in calculating premiums. There is also much controversy about the possibility of law enforcement agencies acquiring genetic data collected for health research. Some early studies suggest that a person’s microbiome may also be a unique identifier. And there is the possibility that microbial DNA may contain even more information about a person than does their human DNA. For example, a person’s microbiome signature may contain information about his or her country or region of origin, and might even prove presence in a certain place, if soil or water microbes unique to that location are detected. This kind of information may be sensitive for many reasons, most notably because of the obvious value such information might have for law enforcement purposes. Ethical challenges also arise, for example, in ensuring the privacy and confidentiality of individuals whose microbiome is analyzed for research purposes.

At the moment, many of these considerations are hypothetical. However, as human microbiome research progresses, these questions will become increasingly salient. And as scientific consensus emerges on such critical issues as the stability of the microbiome and the long-term implications of infants’ exposures to antibiotics and probiotics, corresponding advances need to be made in thinking about the ethical implications and frameworks to be developed.

And also this headline, “Microbiome sequencing offers hope for diagnostics“.

antibiotics: sulfa drugs

A few years ago during a visit to the hospital, I was infected with a MRSA, or multidrug-resistant Staphylococcus aureus. MRSA refers to any strain of the staphylococcus bacteria that doesn’t respond to treatment with many commonly used antibiotics. Luckily the strain that infected me wasn’t especially virulent; on a return trip the doctor prescribed a sulfamethoxazole & trimethoprim and sent me on my way. The infection cleared soon after.

Figure 1. Structure of sulfamethoxazole

Sulfamethoxazole (see figure above) belongs to a class of drugs called sulfonamides, or sulfa drugs. These drugs were some of the first antimicrobial treatments and have been used clinically for more than 70 years. So I was intrigued to come across this paper in Science detailing their mechanism of action as I assumed this had been figured out long ago.

The researchers focused their attention on the enzyme dihydropteroate synthase. This enzyme catalyzes an important reaction in the synthesis of folic acid, which is a B-vitamin microbes need to synthesize their DNA and some amino acids. Using X-ray protein crystallography, they were able to look at the structure of dihydropteroate synthase enzymes from B. anthracis and Y. pests bacteria. To see how the enzyme functions they added two molecules to the protein mixture — 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPP) and para-aminobenzoic acid (see Figure 2). This allowed them to examine the enzyme in its most natural state.   The crystal structures with para-aminobenzoic acid and DHPP are bound show that two loops that stabilize intermediates and facilitate product formation. Mutating certain residues in these loops can prevent DHPP or para-aminobenzoic acid from binding.

Figure 2. Structures of DHPP and para-aminobenzoic acid

Later, they added the sulfa drug sulfamethoxazole and they were able to compare how this molecule bound the enzyme versus the two natural ligands. The crystal structures revealed that sulfamethoxazole binds to the protein in a region that overlaps with the binding site of para-aminobenzoic acid. However, sulfamethoxazole extends outside of the binding pocket in such a way that mutating residues in the two loops completely prevents the  drug from binding. Mutating the residues Phe33, Thr67, and Pro69  in the loops were specifically mentioned as being linked to sulfa drug resistance. These results provide insight into how microbes become resistant to drugs and also may be able to help identify newer antibiotics.

Reference: M-K Yun et al., “Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase”. Science (2012), 335, p1110-1113.

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