Persister Cells and the Paradox of Chronic Infections
I hardly ever come here these days, so I apologise if this article has already been posted, but just in case it hasn't... here it is
Persister Cells and the Paradox of Chronic Infections
Dormant persister cells are tolerant to antibiotics and are largely responsible for recalcitrance of chronic infections Kim Lewis Kim Lewis is a Professor in the Department of Biology, and Director of the Antimicrobial Discovery Center, Northeastern University, Boston.
Author Profile--Lewis: From Russia with Love, Particularly for Microbiology
· Both bacteria and fungi produce small numbers of dormant persister cells whose function is survival. · Persisters are not mutants, but phenotypic variants of the wild type, and are tolerant to killing by antibiotics. · Toxin/antitoxin modules function as persister genes. · Antimicrobial therapy selects for high persistence mutants. Chronic infections are often caused by pathogens that are susceptible to antibiotics, but the disease may be difficult or even impossible to eradicate with antimicrobial therapy. This paradox has been known for a very long time, and a solution appears to be in sight. Many recalcitrant chronic infections are associated with biofilms-communities of microorganisms that tend to adhere to surfaces and are enclosed in a layer of exopolymers. Biofilms form on indwelling medical devices or within tissues and are responsible for infections of catheters, orthopedic prostheses, heart valves, middle ear (otitis), unhealing wounds, and lungs of patients with cystic fibrosis (CF). These infections may require surgery to remove a heart valve or prosthesis, and ultimately cause the death of CF patients. How are biofilms able to resist killing by antibiotics? Early attempts to explain biofilm resistance to killing failed to pinpoint a specific mechanism, resulting in the popular idea that recalcitrance is multicomponent. The usual suspects include retarded penetration of drugs through the exopolymer matrix, slow growth of cells, and antibiotic resistance mechanisms that are specifically expressed in the biofilm. Yet it appears that the main culprit may have been overlooked. A decade ago, our group was studying killing of biofilms of Pseudomonas aeruginosa, the principal pathogen in CF infections, by antibiotics and noticed that death of cells was distinctly biphasic (Fig. 1A). Most cells in the biofilm were readily killed at low concentrations of antibiotics, but a small subpopulation appeared invincible. It seemed clear that these persister cells, rather than the bulk, were responsible for the infection's recalcitrance. Originally described by Joseph Bigger in 1944 in the study of a planktonic population of Staphylococcus, persister cells remained a mere curiosity to the small number of experts who knew of their existence. Rediscovering persisters in biofilms, and the intriguing possibility that these cells are the main culprit of recalcitrant chronic infections, renewed our interest in understanding the nature of these unusual cells.
(...the whole article can be read at link above)
Prospects for Persister Eradication The incidence of chronic infections in the developed world is comparable to acute infections, but we do not have a single agent capable of effectively eliminating dormant cells. In part, this is due to the FDA requirement to test new drugs against exponentially growing pathogens. Most antibiotics would fail if tested against stationary cells, and all will fail if tested against persisters. While resistance is a serious problem, we do have a very large arsenal of antibiotics to treat pathogens in acute infections. Knowing that persisters are largely responsible for recalcitrance of chronic infections is an important first step to developing therapeutic agents, but the road will not be easy-developing an antibiotic even in an "easy" case of a narrow-spectrum compound acting against exponentially growing cells is extremely difficult. Only three novel compounds have been developed over the past 30 years-linezolid (oxazolidinone), daptomycin (peptidolipid), and synercid (Quinupristin/dalfopristin). All three act only against gram-positive species. Multidrug-resistant, gram-negative pathogens such as P. aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, and Klebsiella pneumoniae are becoming major problems, with no new drugs in sight. An overreliance on the major source of antibiotics- cultivable bacteria- reduced the pace of discovery to a trickle by the early 1960s. Gram-negative pathogens have a formidable penetration barrier made of two membranes and transenvelope MDR pumps that export amphipathic compounds across this barrier. Synthetic drugs are almost invariably extruded by the MDRs. Add these difficulties to the need to kill dormant cells which form by redundant mechanisms, and the prospect of eradicating a chronic infection appears bleak. A possible solution may lie in the mode of action of a minor group of antibiotics that are very different from conventional target-specific compounds. These are prodrugs, used now primarily as anti-TB therapeutics. Compounds such as isoniazid (INH) or ethionamide are activated by bacteria-specific enzymes into reactive compounds. Metronidazole is the only known broad-spectrum prodrug, being activated by nitrate reductase, which is present in many bacteria. The beauty of prodrugs is that they can in principle kill dormant cells, since a reactive molecule can disrupt such cellular components as the membrane and DNA, and their covalent binding to targets produces an irreversible sink, countering efflux. Indeed, metronidazole is highly effective against gram-negative species, but its application is limited to anaerobic conditions where nitrate reductase is expressed. Known prodrugs do not sterilize an infection, but their mode of action carries the promise of developing compounds with a better fit to their activating enzyme, which may produce sufficient amounts of reactive compounds that will kill persisters.
ACKNOWLEDGMENTS Kim Lewis is supported by grants from the National Institutes of Health, the Army Research Office, and the Bill and Melinda Gates Foundation.