Retapamulin - How a mushroom fights bacteria

Pleurotus mutilus (also called Clitopilus scyphoides) is delicate cream-coloured edible ectomycorrhizal gilled mushroom that makes an antibacterial compound quite aptly called pleuromutilin.

Like many other antibiotics, pleuromutilin and its lab-born derivatives carry out bacterial genocide by binding to bacterial ribosomes and inhibiting protein synthesis (which is what ribosomes do). This is accomplished by their binding to a domain of 23S rRNA (ribosomes = protein + rRNA), not bound by any other type of similar-acting antibiotic, and directly preventing the binding of the components (peptidyl transferase and amino acid-carrying tRNAs) binding necessary for the formation of proteins. Their unique site of action means that cross-resistance to other antibiotics is non-existent, making them effective against things like MRSA.

Retapamulin (Altabax, Altargo) is a topical semisynthetic pleuromutilin derivative formulated as an ointment and indicated for the treatment of superficial bacterial skin infections such as impetigo and those resulting from wounds. It works well against Gram-positive bacteria, but not much else. Other pleuromutilins that are out there include tiamulin and valnemulin, which are both used by veterinarians to treat infected pigs.

- Yan K, Madden L, Choudhry AE, Voigt CS, Copeland RA, Gontarek RR. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother. 2006 Nov;50(11):3875-81. Epub 2006 Aug 28.
- Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs. 2008;68(6):855-73.

Aztreonam - The lonely monobactam from a purple bacterium

I appear to be on a bit of an obscure antibiotic kick right now, so bear with me!

In 1928, a Scotsman named Alex Fleming discovered that a mould contaminating one of his Petri plate-based bacterial cultures was dissolving the bacterial colonies around it as it grew. Fortunately for us all, he decided to play around with the mould and managed to extract an antibacterial substance that he boringly named penicillin, after the genus of mould that produced it. It was subsequently shown to be highly effective at treating bacterial infections in humans. World War II came along, spurring the development of a means of mass-production of the drug and ultimately saving the lives of a huge number of infected Allied soldiers. Penicillin went on to revolutionize the treatment of bacterial infections worldwide. The functional group in penicillin that enables it to smite bacteria is the beta-lactam ring. This ring is only four-sided, making it relatively unstable and permitting it to bind to and inactivate an enzyme necessary to make a strong bacterial cell wall. Affected bacteria with wussed-out walls are killed by the uncontrolled buildup of osmotic pressure, which generally causes them to pop/burst/rupture.

Approximately one zillion derivatives of penicillin have since been developed in an attempt to increase the range of bacteria that it can fight and improve its pharmacokinetics (essentially, its ability to get to the site of infection at a high enough concentration to do its thing) and safety. Further research in the realm of microbe-produced antibiotics has yielded a slew of other beta-lactam ring-containing classes of drugs. These include cephalosporins (original compound is produced by fungi of the genus Acremonium), cephamycins (produced by bacteria of the genus Streptomyces), cephabacins (produced by several bacteria of the family Xanthomonadaceae), carbapenems (based on thienamycin, a product of the bacterium Streptomyces cattleya), nocardicins (produced by the bacterium Nocardia uniformis), and monobactams (produced by the bacteria Chromobacterium violaceum).

The monobactams are neat because a) only one of them (aztreonam) has actually been developed into a commercially available drug and b) their beta-lactam ring is not fused to another ring, as it is in all of the other classes except the nocardicins. The natural synthesizer of aztreonam (Azactam), Chromobacterium violaceum, is a Gram-negative rod-shaped bacteria found in water and soil all over the world that occasionally infects humans. When grown in culture, it produces distinctive smooth metallic dark violet colonies, reflecting the production of a pigment called violacein, which is capable of killing amoebae and trypanosomes. C. violaceum also produces other antibiotics, including aerocyanidine and aerocavin. Unlike the penicillins, aztreonam is lousy at binding to and destroying gram-positive and anaerobic bacteria. However, it has good activity against most aerobic gram-negative bacteria, including those belonging to the genus Pseudomonas. In the clinic, aztreonam must be injected. An inhaled form has been developed (based on the use of an ultrasonic nebulizer to render a solution of the drug airborne as a mist) and is currently in trials.

- Aoki H, Sakai H, Kohsaka M, Konomi T, Hosoda J. Nocardicin A, a new monocyclic beta-lactam antibiotic. I. Discovery, isolation and characterization. J Antibiot (Tokyo). 1976 May;29(5):492-500.
- Durán N, Menck CF. Chromobacterium violaceum: a review of pharmacological and industiral perspectives. Crit Rev Microbiol. 2001;27(3):201-22. Review.
- Hellinger WC, Brewer NS. Carbapenems and monobactams: imipenem, meropenem, and aztreonam. Mayo Clin Proc. 1999 Apr;74(4):420-34. Review.
- Ono H, Nozaki Y, Katayama N, Okazaki H. Cephabacins, new cephem antibiotics of bacterial origin. I. Discovery and taxonomy of the producing organisms and fermentation. J Antibiot (Tokyo). 1984 Dec;37(12):1528-35.

Mupirocin

Pseudomonas fluorescens is a common nonpathogenic Gram-negative bacteria found in poop, soil, and water that gets its name from the fact that it secretes a fluorescent siderophore (iron-binding compound) called pyoverdin (fluorescein). Cultures of it glow under black light, making it the raver's bacterium of choice. P. fluorescens also produces an epoxide antibiotic, originally named pseudomonic acid A but commonly called mupirocin (trade names Bactroban or Centany), that is good at inhibiting the growth of and outright killing (at higher concentrations) Gram-positive bacteria, particularly staphylococci and streptococci.

Mupirocin is typically formulated as a topical cream, ointment, or spray used to treat infections of the skin (e.g. boils, impetigo, the likely consequence of not bothering to clean a dirty scrape on your knee, etc.). It can only be used topically (i.e. applied to the surface of the body) because it is rapidly and extensively broken down once it gets into the blood and interstitial fluid. Notably, it is capable of killing methicillin-resistant Staphylococcus aureus (MRSA), and has been used to treat nasal carriers of this bacterium in addition to those infected with it. Although resistance to mupirocin is more or less inevitable, limiting its use could prolong its usefulness until resistant bacteria become widespread.

The ability of mupirocin to extirpate bacteria that are resistant to other antibiotics is due to its novel mechanism of action, which involves the inhibition of the enzyme isoleucyl-tRNA synthetase, which is responsible for attaching the amino acid isoleucine to its corresponding transfer RNA . Bacteria need this amino acid to make proteins. Most antibiotics mess with either the bacterial cell wall or the synthesis of bacterial DNA or proteins, so hitting the bacteria at the amino acid level is something different.

- Parenti MA, Hatfield SM, Leyden JJ. Mupirocin: a topical antibiotic with a unique structure and mechanism of action. Clin Pharm. 1987 Oct;6(10):761-70. Review.

Puerarin - Good for hearts and hangovers

Kudzu (Pueraria lobata) is a fast-growing and incredibly resilient invasive climbing vine that was introduced to North America from its native habitat in East Asia. This plant is an intense sonofabitch, being capable of growing at a rate of up to 30 centimetres (inches) per day. It has been known to smother forests with its growth, and is taking over the American south as we speak. The purple flowers of the plant are used to make a scrumptious jelly, and the leaves and roots can be eaten.

Kudzu produces a number of isoflavones, organic compounds with rings and stuff that are typically strong antioxidants (may reduce tissue damage by free radicals, which are produced as a part of normal metabolic activity) and capable of mimicking the effects of estrogen in mammals (phytoestrogens).

Puerarin is the most concentrated isoflavone found in kudzu. This makes it the major active ingredient in Ge-gen, a traditional Chinese medicine made from kudzu root. Ge-gen is used traditionally to treat fever, pain, diabetes, measles, diarrhea, and cardiovascular diseases including coronary artery disease, arrhythmia and hypertension. It also has been employed as a means of relieving drunkenness and hangover after a long night on the town.

Interestingly, puerarin is capable of selectively suppressing alcohol intake in animal models of excessive drinking (rats and monkeys), suggesting that it may have application as a drug therapy for alcoholism (anticraving agent). It is thought to reduce alcohol absorption by inhibiting the movement of alcohol across gut membranes, thus reducing blood alcohol levels.

- Rezvani AH, Overstreet DH, Perfumi M, Massi M. Plant derivatives in the treatment of alcohol dependency. Pharmacol Biochem Behav. 2003 Jun;75(3):593-606.
- Zhang SY, Chen G, Wei PF, Huang XS, Dai Y, Shen YJ, Chen SL, Sun-Chi CA, Xu HX. The effect of puerarin on serum nitric oxide concentration and myocardial eNOS expression in rats with myocardial infarction. J Asian Nat Prod Res. 2008 Apr;10(4):323-8.