MINITOPIC
`Shapes and Curves; Plus Revised View
`of Cell-Wall Growth
`
`The shapes of microbial species are sometimes fanciful and can be important for
`their survival or may mask activities that are key to physiology. Recent examples
`include:
`• Helicosporidium, a corkscrew-shaped intracellular parasite that feeds on juve-
`nile insects, derived from algae but, unlike Plasmodium, the parasite responsi-
`ble for malaria which also derived from algae, retained most of its genes except
`those explicitly needed for photosynthesis, according to Patrick Keeling of the
`University of British Columbia (BC)
`in Vancouver, B.C., Canada, and his
`collaborators. Details appeared 8 May 2014 in PLoS Genetics (doi:10.1371
`/journal.pgen.1004355).
`• In gently moving water, the curvature of Caulobacter crescentus cells helps to
`point progeny swarmer cells toward the surface, where they go to attach to
`similar cells, enlarging the growing colony, according to Alexandre Persat and
`Zemer Gitai at Princeton University and their collaborators. Details appeared 8
`May 2014 in Nature Communications (doi:10.1038/ncomms4824).
`• The cell wall enzyme PBP2 and the bacterial actin homolog MreB are active on
`drastically different time scales, suggesting that cell wall growth in gram-
`negative bacteria depends on dynamic instead of stable complexes involving
`these and other proteins, according to K. C. Huang of Stanford University in
`Stanford, Calif., and his collaborators. Thus, for example, the cell wall keeps
`growing under osmotic stress but the new segments remain shriveled until
`conditions allow them to expand and take their rightful shape. Details
`appeared 12 May 2014 in the Proceedings of the National Academy of Sciences
`(doi:10.1073/pnas.1313826111).
`
`WHO takes great pains not to em-
`barrass individual countries for how
`well or poorly they “measure up,” and
`this low-key approach ends up being a
`“core problem,” Fineberg says. Al-
`though the idea of WHO helping in
`efforts to assess a country’s capacity to
`deal with emerging infectious diseases
`“makes sense, national governments
`don’t like it,” Fukuda adds, noting that
`only about 20% of the countries have
`the appropriate capacity. “WHO is
`well-positioned to help with quality as-
`sessments, but we haven’t found the
`right way to achieve the necessary po-
`litical balance.”
`Another looming issue is how best
`to deal with the Convention on Biolog-
`ical Diversity (CBD), an international
`agreement from 1992 that was never
`intended to deal with public health is-
`sues. Nonetheless, some of its provi-
`
`sions bump into matters concerning
`IHR 2005, particularly when it comes
`to sharing of biological materials that,
`for example, might prove critical for
`the development of diagnostic tests
`and vaccines. “What can you do?” Fu-
`kuda asks. “This framework [the CBD]
`is seen as being ‘over there,’ having
`nothing to do with health, but we real-
`ize it does.”
`Jeffrey L. Fox is the Microbe Current Topics and
`Features Editor.
`
`NEW IN ASM JOURNALS
`Freely Diffusing
`Topical Antifungal Agent
`Fixes Infected Toenails
`David C. Holzman
`The candidate antifungal drug efına-
`conazole is proving effective against
`toenail infections. The drug diffuses
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`CURRENT TOPICS
`
`relatively freely through nails and
`binds less strongly to keratin than do
`other
`topically
`applied antifungal
`drugs, leaving it free to fıght the fungus,
`according to Keita Sugiura of Kaken
`Pharmaceutical of Kyoto, Japan, and
`his collaborators. “This study suggests
`that . . . low keratin affınity is needed
`for favorable penetration and retention
`of antifungal activity within the nail
`matrix,” he says. Details appeared on-
`line 21 April 2014 and will be printed in
`the July 2014 Antimicrobial Agents and
`Chemotherapy.
`Because topical antifungal drugs so
`often fail to cure this condition, physi-
`cians sometimes prescribe oral anti-
`fungal drugs such as terbinafıne and
`itraconazole for some of their patients
`with stubborn cases of onychomycosis.
`However, Sugiura points out, this ap-
`proach “is limited” because such drugs
`can damage the liver or may interact
`with other drugs that patients are tak-
`ing. Although topically applied anti-
`fungal drugs such as ciclopirox and
`amorolfıne have “a favorable safety
`profıle,” he adds, “their cure rates are
`considerably lower.”
`Sugiura and his collaborators tested
`human nails to fınd how well the drug
`diffuses through keratin-rich nails.
`Small 16 mm2 squares from commer-
`cially available toenail material (who
`knew?) were mounted in Franz diffu-
`sion cells to measure how quickly sev-
`eral antifungal drugs pass through that
`material. Efınaconazole proved speedi-
`est, racing through the mounted nail
`squares within the fırst day, while
`ciclopirox took six days and amorolfıne
`remained undetected, they report.
`Of several drugs tested, only efına-
`conazole inhibited fungal growth un-
`der nails in vitro, according to Sugiura.
`He and his collaborators also tested the
`fungicidal activity of several topical an-
`tifungal products in a fluid keratin me-
`dium that is designed to “mimic the
`keratin-rich environment of the nail
`plate and nail bed.” Without a solid ma-
`trix to block the drugs, efınaconazole
`proved slightly more potent at killing
`
`Microbe—Volume 9, Number 7, 2014
`
`• 267
`
`

`

`CURRENT TOPICS
`
`Fungal infections of toenails are particularly difficult to
`treat, chiefly because it is difficult to get antifungals to
`penetrate the nail. A new topical antifungal, efinacona-
`zole, shows good penetration into infected nails and may
`be a breakthrough for treating infections that previously
`could only be treated with orally administered drugs.
`(Image © iStockphoto/4kodiak.)
`
`the fungus than did amorolfıne and far
`more potent than ciclopirox, they note.
`“Efınaconazole is the fırst topical
`drug that has shown effıcacy for this
`persistent and common infection,”
`says Boni Elewski of the University of
`Alabama, Birmingham, who last year
`led a pair of phase 3 clinical studies to
`evaluate this drug for treating onycho-
`mycosis, the formal name for chronic
`fungal infections of toenails. “I think
`this mechanism of action is indeed
`quite signifıcant, contributing to the rel-
`atively high mycologic cure rate in treat-
`ing onychomycosis,” says Elewskii.
`The typical fungi responsible for on-
`include Trichophyton
`ychomycosis
`rubrum, T. mentagrophytes, Candida
`albicans, and nondermatophyte molds.
`The condition affects about 8% of the
`U.S. population, mainly adults, partic-
`ularly those who are 60 years of age or
`older. While more a cosmetic than a
`frank health issue, onychomycosis can
`prove painful as well as being an eye-
`sore, and may interfere with work that
`entails standing, food handling, mod-
`eling, or other interactions and rela-
`tionships, Elewski points out.
`David C. Holzman is the Microbe Journal
`Highlights Editor.
`
`268 • Microbe—Volume 9, Number 7, 2014
`
`RESEARCH ADVANCES
`Promising
`Tuberculosis
`Drug also Targets
`Vastly Different
`Microbes
`Carol Potera
`A promising candidate drug
`for
`treating tuberculosis
`(TB), called SQ109 and un-
`dergoing phase 2 clinical
`trials, acts against Myco-
`bacterium tuberculosis as
`well as other microbial
`pathogens and parasites via
`several different mecha-
`nisms, according to Eric
`Oldfıeld at the University
`of Illinois, Urbana-Cham-
`paign, and his collabora-
`tors. Not only SQ109, but also a series
`of analogues inhibit the growth of a
`range of microorganisms, acting at var-
`ious molecular
`targets—leading to
`“very low rates of spontaneous drug
`resistance,” they report. “There’s an ur-
`gent need for new drugs that are resis-
`tance-resistant, and drugs that hit mul-
`tiple targets will reduce resistance,”
`Oldfıeld adds. Details appeared Febru-
`ary 25, 2014 in the Journal of Medicinal
`Chemistry (doi:10.1021/jm500131s).
`SQ109 is a 1,2-diamine that is re-
`lated to ethambutol, a widely used drug
`that is bacteriostatic against M. tuber-
`culosis, blocking cell-wall production.
`Sequella, Inc. in Rockville, Md., a com-
`pany focused on TB, began developing
`SQ109 in 2000, then in partnership
`with researchers at the National Insti-
`tutes of Health (NIH)
`in nearby
`Bethesda, Md. Several years ago, mem-
`bers of the NIH group and their collab-
`orators reported that SQ109 “interferes
`with the assembly of mycolic acids into
`the cell wall core of M. tuberculosis.”
`They also concluded that the primary
`bacterial
`target
`for
`the drug was
`MmpL3, “a transporter of trehalose
`monomycolate,” an ingredient of the
`cell wall in M. tuberculosis.
`That seeming clarity for how SQ109
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`MINITOPIC
`Synthetic Biology:
`Microbe Reaches First
`Base with Odd
`Nucleotides
`
`An engineered version of Escherichia
`coli can grow normally while stably
`carrying unnatural nucleotide base
`pairs within a replicating plasmid,
`according to Floyd Romesberg of
`the Scripps Research Institute in La
`Jolla, Calif., and his collaborators.
`Triphosphate versions of those un-
`natural
`base
`pairs,
`designated
`d5SICS and dNaM, are brought into
`the E. coli bacterial cells via an algal
`transporter protein, and the DNA
`replication machinery of those cells
`“uses them to accurately replicate a
`plasmid,” they report. The bacterial
`DNA repair apparatus leaves the al-
`tered plasmids alone, and the addi-
`tion of
`the synthetic base pairs,
`which are not being translated into
`novel amino acids, does not appear
`to slow down the growth of the
`altered cells. Their next step in this
`research, Romesberg and his collab-
`orators say, “will be to demonstrate
`the in-cell transcription of the new,
`expanded-alphabet DNA into the
`RNA that feeds the protein-making
`machinery of cells.” Details ap-
`peared May 7, 2014 in Nature (doi:
`10.1038/nature13314).
`
`and analogues like it work, however,
`proved to be less than complete. Other
`researcher groups reported that SQ109
`acts against other microbial species, in-
`cluding Helicobacter pylori bacteria
`and Candida albicans, a yeast. Neither
`one of them produces the MmpL3
`transporter or makes cell walls like
`those of M. tuberculosis. Those and
`other results suggest that there must be
`other cellular targets for SQ109 and its
`analogues.
`Oldfıeld and his collaborators tested
`SQ109 and a series of analogues against
`a battery of fıve bacteria, including M.
`
`