No vacationing tourists take passage for the sun, sea, sand and palm trees of the Pathogenicity Islands.

These romantically named genomic structures visit virulent infections on people unlucky enough to be attacked by the intestinal bacterium Enterococcus faecalis. That microorganism's pathogenicity island consists of a self-contained assembly of 129 genes measuring 150,000 base pairs in size. A goodly proportion of those genes function as virulence factors.

This grimly effective bacterial drug resistance fights off one antibiotic in particular - vancomycin. In bygone decades, vancomycin kept E. faecalis safely at bay, but now that gut bug is the second deadliest infectious organism in American hospitals. Microbial pathogeneticist Nathan Shankar, at the University of Oklahoma, recalls that nosocomial denouement:

"We were studying genes in close proximity to the surface protein of the 'coccus, and looked at the first vancomycin-resistant strain. It was isolated for the first time in the U.S. back in 1983, at Barnes Hospital in St. Louis, and caused a large-scale epidemic in the wards. Then, a few years later - still in the 1980s - another isolate caused a similar outbreak 400 miles away from St. Louis at the University of Wisconsin hospital. That caused 30 to 40 intractable blood infections in the wards - carrying a five-fold risk of death within three weeks.

"Vancomycin doesn't have to get into the bacterial cell wall," Shankar observed. "It actually acts on the cell wall itself. But the bacteria - the resistance ones - have acquired new genes, by which they can alter the structure of its cell wall, so it's no longer susceptible to the action of vancomycin.

"All these epidemic isolates contained the genes of this pathogenicity island. Among the 129 genes identified on the island, we found 20 that are totally novel. There are no homologs in other species. So we want to determine their functions - to come up perhaps with new targets for antibacterial development."

Shankar is lead author of a paper in today's Nature, dated June 13, 2002. Its title: "Modulation of virulence within a pathogenicity island in vancomycin-resistant Enterococcus faecalis."

"From the clinical point of view," he told BioWorld Today, "what our study shows is that Enterococcus - as opposed to just picking up one or two random genes which enhance its property to cause disease - now has the ability to collect a bunch of genes in the pathogenicity island. In the form of one single cluster, these genes are enriched among infections derived from patients, as opposed to isolates from the stools of normally admitted individuals. It's very difficult to cure patients who come down with antibiotic resistance to Enterococcal infections. Certain strains in its species have the propensity to cause disease by genes carried on this pathogenicity island. That led us to demarcate very clearly those rogue isolates that contain bits and pieces of the entire island."

Gut Bug Decimates Infected Hospital Wards

"A clinician in the hospital pathological labs," Shankar noted, "typically does a culture and identifies Enterococcus. But now that we know that these rogue, pathogenic strains carry elements of this pathogenicity island, if we can identify a few of these genes in the lab, that might actually dictate the outcome of the clinical management of the disease. It probably means strictly isolating the patient from the highly pathogenic isolate that can get transmitted across patients in the same ward. Enterococcus faecalis can transfer its virulent genes from infected patients to equally infectious Staphylococcus aureus.

"The Gram-positive Enterococcus faecalis commensally inhabits the human gut, as does its Gram-negative neighbor, Escherichia coli," Shankar observed. (Because E. faecalis lurks in human feces it can cause urinary tract infections [UTI], especially in elderly, immunocompromised and catheterized hospital patients.) "In the intensive care ward," he continued, "a majority of patients undergo catheterization, which can cause severe UTI. E. faecalis," he went on, "can escape the gut and enter the bloodstream. There, its bacteremia may cause often-fatal endocarditis. It colonizes the heart valve with bacterial biofilm, which is very difficult, if not impossible, to get rid of.

"As we report in Nature," Shankar said, "our finding suggests that the Esp surface protein, which we identified a couple of years ago, is a major player in biofilm formation by Enterococcus. For example, when the bacterium is in the blood, if it starts to make some of these surface factors, it is quickly detected as a foreign organism by the human immune system, and tends to be rapidly cleared. On the other hand, the surface structures may be needed by the bacteria to translocate from the intestine into the blood. But after that it will be advantageous for the germ to lose these structures, so it can evade the host immune response. Thus, Esp may be a new drug target for antibacterial development."

To Win War, Give Bacterium Its Comeuppance

"One thing we found recently," Shankar added, "is that an Esp homolog also occurs in an Enterococcus species called E. faecieum. So we presume that there has been another pathogenicity island in that species, too - a presumption we are continuing to explore. Another gene carried on E. faecalis' pathogenicity island is cytolysin," he pointed out, "which has the ability to lyse red blood cells. So once the bacterium gets into the bloodstream it can lyse your erythrocytes. This could cause a serious, often fatal, infection."

On a broader horizon, Shankar surveys the present outlook in the world today for the war between antibiotics and drug resistance. "I don't think it's a matter of losing that war," he surmised. "But I do think we have to continue to keep up our efforts to look for new drug targets - new antimicrobials - directed against targets which the bacteria have not been used to seeing in the past. And I think it's a constant race between the bacteria being one up on you and you trying to outdo the bacteria.

"Back in the 1970s and '80s," he recalled, "we thought we had conquered infectious diseases, and didn't have much more need for research in anti-infectives. Instead we turned to concentrate on AIDS and cancer. But I think now we are beginning to realize that this will be a never-ending battle against the bacteria, so we really need to stay one up on them."