Allies and Enemies: How the World Depends on Bacteria (14 page)

nonbacterial diseases in the hope that the drug helped kill secondary

infections even while they knew the primary infection had been caused by a virus. If a doctor noticed that an antibiotic began losing

strength, he would simply prescribe a new antibiotic. Sometimes a patient received both drugs at the same time. Two antibiotics

together stymied bacteria for a while, but this strategy created problems. Any two random antibiotics cannot be paired and expected to

work better than either drug alone. Certain antibiotics lower the activity of the second: streptomycin inhibits chloramphenicol’s

activity; erythromycin blocks penicillin’s activity. When tetracycline acts on
Staphylococcus
, for instance, it inhibits protein synthesis in mature cells. But penicillin requires new, growing cells to exert its activity against the cell wall. By slowing bacteria’s growth, tetracycline neutralizes penicillin’s mode of action.

Multiple antibiotics, even when paired correctly, also led to multidrug resistance. Bacteria now evade many antibiotics at the same time. This is not an extraordinary talent as nature already exposes bacteria to more than one antibiotic or bacteriocin at a time, and multidrug resistance probably already existed in a minority of bacteria. Soil bacteria face a dense community of antibiotic-producing fungi and bacteria that make antibiotic resistance essential for survival. The proliferation of antibiotic use from the 1950s to the1980s merely accelerated the evolution of antibiotic defenses.

Some bacteria began carrying additional resistance genes for

more than one antibiotic. Methicillin-resistant
Staphylococcus aureus
(MRSA) has separate genes that control resistance for the penicillin family of antibiotics as well as genes for resisting tetracycline, clindamycin, aminoglycoside, and erythromycin.

Bacteria with pump mechanisms could eject an antibiotic as soon

as the drug passed through the cell wall and membrane. These bacteria developed more sophisticated systems to resist multidrug treatment with an adaptation called the ABC transporter, for “ATP-binding cassette transporter.” (A cassette is a set of genes that work as a team.) Present in bacteria, archaea, and eukaryotes, ABC transporters are proteins that help pump certain harmful molecules out of the cell.

(Cancers that do not respond to chemotherapy resist the treatment in

part by employing ABC transporters to eject the drug from tumor cells.)

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ABC transporters consist of two proteins that span the bacterial

membrane from the inner surface surrounding the cytoplasm to the

membrane’s outer surface. The two proteins form a pore through the

membrane. By expending energy, the cell uses this pore to expel a variety of chemicals, including more than one type of antibiotic.

About 30 different types of ABC transporters exist among bacteria to

eject from cells the diverse chemicals that can harm them in their environment. In addition to antibiotics and bacteriocins, transporters

carry bile salts, immune system factors, hormones, and carried chemicals called ions, and they have recently been shown to adapt to, and

eject, human-made antibiotics.

Multidrug resistance among bacteria has now become more

prevalent than resistance to a single antibiotic. Some bacteria carry so many defenses it seems as if they were designed specifically to defeat drug companies’ best efforts. The tuberculosis bacterium
Mycobacterium tuberculosis
contains 30 different ABC transporters that provide the species with a defense that acts as a backup to other defensive schemes. First, the microbe’s unusual cell wall composition prevents

the penetration of many antibiotics that work on other bacteria. The

ABC transporter system acts on any antibiotic that manages to get past the cell wall. Second,
M. tuberculosis ’s capability to hide inside cells of the immune system enables it to elude antibiotics circulating the bloodstream. Third, these bacteria grow like the tortoise compared with
E. coli
’s hares. Slow growth may not in itself be a defensive tactic, but this characteristic of the species forces doctors to lengthen the antibiotic treatment for TB. Because most antibiotics work best on actively dividing bacteria,
M. tuberculosis
’s growth rate lessens an antibiotic’s killing efficiency. Typical TB treatment lasts six months or longer, and this alone favors the pathogen because even diligent patients have a hard time staying on a drug regimen for that long.

The multiple defenses of
M. tuberculosis
necessitated more than one antibiotic when doctors began treating the disease with antibiotics in the 1940s. Two antibiotics worked well for many years, but now this species requires four different drugs to kill it, and many strains already resist all four, leaving doctors with a dwindling choice of antibiotics that still work against TB. Like other bacteria, when M. tuberculosis has developed a favorable trait, it keeps the gene for 76

allies and enemies

that trait in its DNA. Multidrug resistance has also become common

in skin infections, sexually transmitted diseases, and pneumonia.

Following Germany’s 1936 introduction of sulfa drugs to cure

gonorrhea, resistant strains of
Neisseria gonorrhoeae
had spread throughout the country by 1942. Doctors turned to penicillin as soon as U.S. drug companies made large quantities available. Before the

1960s had arrived, resistant
N. gonorrhoeae
capable of cleaving penicillin into pieces had spread around the globe. Almost all Staphylococcus species had already become resistant to penicillin 15 years earlier. Bacteria have become so efficient in building and sharing resistance that they no longer need months or years to adapt. Four days after streptomycin therapy begins, for a kidney infection for instance, streptomycin-resistant bacteria outnumber the susceptible

bacteria in patient urine samples.

Bacteria possess an effective defense against antibiotics: the plasmid. Bacteria of the same species or sometimes dissimilar species pass

plasmids back and forth and thereby give each other useful traits they

would not normally possess. Sometimes bacteria insert a resistance

gene from their chromosome into a plasmid before passing the plasmid

to other cells. Cells also share entire DNA segments from the chromosome by absorbing pieces when another cell dies and breaks apart or by

connecting cell-to-cell in a version of bacterial sex.

Microbiologists have tried various approaches to outmaneuver

bacterial defenses against antibiotics. One ploy called the Trojan Horse takes advantage of the competition for iron among living things in nature. Because iron can be scarce in many habitats, bacteria produce compounds called siderophores to seize hold of precious iron molecules and bring the metal into the cell through a specific pore. Microbiologists have designed siderophores that instead of grabbing iron will bind to an antibiotic. When bacteria recognize the siderophore, they open the pore to let it in and thus allow the antibiotic to enter.

If certain bacteria do not fall for the trick of smuggling an antibiotic into their cells, microbiologists try substituting the metal gallium for iron in siderophores—the two metals look similar to bacteria—to derive the bacteria of essential iron.

Microbiologists have another weapon at their disposal in bacteriophages or phages, which are viruses that attack only bacteria.

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In the microbial world, bacteria look like the mother ship to a phage’s fighter jets. A phage measures 225 nanometers (nm) at most at its longest end-to-end distance; a typical bacterial cell volume is 1,300

times the volume of a phage.

Microbiologists have revived Felix d’Herelle’s idea of a century

ago by designing phages to enter bacteria and inactivate bacterial repair kits or shut down antibiotic pumps. This method has already

been tried in humans to correct genetic diseases in the new science

of gene therapy. In gene therapy, molecular biologists engineer viruses that infect humans to contain a specific gene that will repair

a defect in human DNA. They inactivate the virus so that it cannot

cause disease but can still infect the human host. When the engineered virus takes over the cell’s DNA replication, it inserts the new gene into the defective DNA.

Phages built to deliver antibiotics or foil the defenses of resistant

bacteria have not been tried outside laboratory trials. But because of

the constant evolution of bacteria to avoid harm from drugs, biology

must stay abreast with new weapons of its own.

Bacteria share their DNA

Gene transfer confers on bacteria the capability to accept helpful genes from other microbes. In eukaryotes from algae all the way up to

humans, gene transfer occurs by one mechanism, the fusion of

gametes. One gamete from a female and one from a male creates a

zygote that carries the DNA from both parents. Bacteria and archaea

have three major routes whereby they exchange genes: transformation,

transduction, and conjugation. All of these methods are called horizontal gene transfer because they occur between two or more adult cells

rather than the standard sharing of genes by producing daughter cells.

Transformation occurs when bacteria take in DNA directly from

the environment. The DNA may be either the molecule from the

nucleoid or a plasmid. In either case, the DNA dissolves in an aqueous

environment when a cell dies and lyses. A live bacterial cell encountering the DNA in its habitat may attach to the molecule and use an

enzyme to unravel the large polymer. DNA is a double-stranded

structure resembling a ladder. The enzyme cuts the ladder’s rungs to

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allies and enemies

separate the DNA in half. One half degrades, but the cell pulls the

other half inside where it will incorporate it into its own DNA.

Transduction occurs when a bacteriophage infects a bacterial cell

and brings DNA from another microbe with it. If the phage comman—

deers the cell’s DNA replication steps but does not kill the bacterium, the bacterial cell makes new progeny containing some of the foreign DNA. New bacteria never before seen in nature begin growing.

When plasmids transfer between cells, they do so by conjugation.

Conjugation has been called the bacterial version of sexual reproduction because two cells physically connect with one another by a tube

called a sex pilus. After DNA has moved through the pilus from the

first cell to the second, the pilus breaks. As a result of conjugation, the receptor cell incorporates new genes into its existing DNA. When the cell divides, the daughter cells and each successive generation can carry these genes.

Gene transfer in bacteria has its most profound effects in allowing antibiotic-resistance genes to move through a population of bacteria. The bacteria need not be closely related as long as they can use one of the three methods described above for passing DNA back and

forth. Since plasmids have been shown to carry multiple genes for antibiotic resistance, plasmid transfer may be a major route for the

expansion of antibiotic resistance in the past few decades. Biologists

have not answered all their questions on the evolution of gene transfer in bacteria, but there can be no question of the advantages these

systems give to bacteria.

The opportunists

Hospitals act as hot spots for antibiotic-resistant bacterial infections because hospital settings have high antibiotic use and a patient community weakened by disease, trauma, or surgery. These circumstances open the opportunities for bacterial infection. Nosocomial infections are infections picked up in hospitals. Many of these infections could

well come from doctors, nurses, technicians, and other hospital staff

who do not wash their hands properly between patient visits. Secret

observations of hospital staff have revealed that healthcare professionals wash their hands properly only slightly more often than the general chapter 3 · “humans defeat germs!” (but not for long)

79

public of which less than 50 percent wash properly. Most of these poor

habits (not enough time washing hands, not enough soap, no soap, or no

hand wash at all) occurred in the public restroom! Most hospitals now

have resident bacteria in proportions found nowhere else in society, and these nosocomial populations have a high incidence of multidrug resistance. No wonder that people believe that any bacterium is a dangerous bacterium. This thinking spawned not only antibiotic misuse, but a similar overuse of disinfectants and other antimicrobial products.