Escherichia coli requires FtsZ, FtsA and ZipA proteins for early stages of cell division, the latter two tethering FtsZ polymers to the cytoplasmic membrane. Hypermorphic mutants of FtsA such as FtsA* (R286W) map to the FtsA self-interaction interface and can bypass the need for ZipA. Purified FtsA forms closed minirings on lipid monolayers that antagonize bundling of FtsZ protofilaments, whereas FtsA* forms smaller oligomeric arcs that enable bundling. Here, we examined three additional FtsA*-like mutant proteins for their ability to form oligomers on lipid monolayers and bundle FtsZ. Surprisingly, all three formed distinct structures ranging from mostly arcs (T249M), a mixture of minirings, arcs and straight filaments (Y139D) or short straight double filaments (G50E). All three could form filament sheets at higher concentrations with added ATP. Despite forming these diverse structures, all three mutant proteins acted like FtsA* to enable FtsZ protofilament bundling on lipid monolayers. Synthesis of the FtsA*-like proteins in vivo suppressed the toxic effects of a bundling-defective FtsZ, exacerbated effects of a hyper-bundled FtsZ, and rescued some thermosensitive cell division alleles. Together, the data suggest that conversion of FtsA minirings into any type of non-miniring oligomer can promote progression of cytokinesis through FtsZ bundling and other mechanisms.
As Mycoplasma pneumoniae macrolide resistance grows and spreads worldwide, it is becoming more important to develop new drugs to prevent infection or limit disease. Because other mycoplasma species have acquired resistance to other classes of antibiotics, it is reasonable to presume that M. pneumoniae can do the same, so switching to commonly used antibiotics like fluoroquinolones will not result in forms of therapy with long-term utility. Moreover, broad-spectrum antibiotics can have serious consequences for the patient, as these drugs may have severe impacts on the natural microbiota of the individual, compromising the health of the patient either short-term or long-term. Therefore, developing narrow-spectrum antibiotics that effectively target only M. pneumoniae and no more than a small portion of the microbiota is likely to yield impactful, positive results that can be used perhaps indefinitely to combat M. pneumoniae. Development of these agents requires a deep understanding of the basic biology of M. pneumoniae, in many areas deeper than what is currently known. In this review, we discuss potential targets for new, narrow-spectrum agents and both the positive and negative aspects of selecting these targets, which include toxic molecules, metabolic pathways, and attachment and motility. By gathering this information together, we anticipate that it will be easier for researchers to evaluate topics of priority for study of M. pneumoniae.
Although mycoplasmas have small genomes, many of them, including the HIV-associated opportunist Mycoplasma penetrans, construct a polar attachment organelle (AO) that is used for both adherence to host cells and gliding motility. However, the irregular phylogenetic distribution of similar structures within the mycoplasmas, as well as compositional and ultrastructural differences among these AOs, suggests that AOs have arisen several times through convergent evolution. We investigated the ultrastructure and protein composition of the cytoskeleton-like material of the M. penetrans AO with several forms of microscopy and biochemical analysis, to determine whether the M. penetrans AO was constructed at the molecular level on principles similar to those of other mycoplasmas, such as Mycoplasma pneumoniae and Mycoplasma mobile. We found that the M. penetrans AO interior was generally dissimilar from that of other mycoplasmas, in that it exhibited considerable heterogeneity in size and shape, suggesting a gel-like nature. In contrast, several of the 12 potential protein components identified by mass spectrometry of M. penetrans detergent-insoluble proteins shared certain distinctive biochemical characteristics with M. pneumoniae AO proteins, although not with M. mobile proteins. We conclude that convergence between M. penetrans and M. pneumoniae AOs extends to the molecular level, leading to the possibility that the less organized material in both M. pneumoniae and M. penetrans is the substance principally responsible for the organization and function of the AO.IMPORTANCE Mycoplasma penetrans is a bacterium that infects HIV-positive patients and may contribute to the progression of AIDS. It attaches to host cells through a structure called an AO, but it is not clear how it builds this structure. Our research is significant not only because it identifies the novel protein components that make up the material within the AO that give it its structure but also because we find that the M. penetrans AO is organized unlike AOs from other mycoplasmas, suggesting that similar structures have evolved multiple times. From this work, we derive some basic principles by which mycoplasmas, and potentially all organisms, build structures at the subcellular level.KEYWORDS Mycoplasma, cytoskeleton, electron microscopy, evolution, fractionation, mass spectrometry, transcriptomics
M ycoplasma canis infects many mammalian hosts but is usually thought of as a commensal or opportunistic cofactor in respiratory or urogenital tract diseases of dogs (1). We found unexpectedly that M. canis was also detectable by culture or PCR in a majority of brain tissue specimens in a retrospective case-control study of canine granulomatous meningoencephalitis (ME) (GME) and necrotizing ME (NME) (2). The presence of M. canis in brain tissue was associated with both GME and NME (both P Ͻ 0.05, as determined by a 2 test). The clinical signs of this common idiopathic neurological disease of dogs include seizures, proprioceptive deficits, circling, and blindness. Immunosuppressive therapy may be palliative, but the syndrome is progressive and uniformly fatal (3). The extensive search for a presumed viral cause of canine GME and NME has been fruitless (4).In humans, bacterial meningitis and encephalitis are multifactorial lethal infections with often severe sequelae for survivors. New detection methods have shown that the variety of bacteria associated with human ME is much more extensive than usually appreciated (5-9). Additional animal models of bacterial ME are necessary to study this broader spectrum of pathogens (10). Since a possible association between M. canis and canine ME was discovered, our objective has been to help fill the void of basic knowledge about the organism's virulence factors, the host responses that it elicits, and its potential roles in pathogenesis. Our working hypotheses were that M. canis is capable of evoking host cell responses that favor dissemination from mucosal surfaces to secondary sites of infection, possibly in a strain-dependent fashion, and also that, regardless of how it might reach those sites, the presence of M. canis there modulates inflammation and direct injury to host cells. Understanding this potential can be expected to help evaluate the cause of canine ME and other diseases.(Portions of these data were presented in abstract form at Congresses of the International Organization for Mycoplasmology [90,91].) MATERIALS AND METHODSMycoplasma strains and cultivation. Strain PG14 T of M. canis (ATCC 19525) was first isolated from the throat of a normal dog (11). Strains UF31, UF33, LV, 5, 26, Cal, and Mara were first isolated from vaginal swabs of dogs without ME (12). Strains UFG1, UFG2, UFG3, and UFG4 were isolated from frozen brain tissues from cases of canine NME (2). Mycoplasma cynos strain H-831 T (ATCC 27544) was first isolated from the lung of a dog with pneumonia (13). Mycoplasma arginini strain G230 T , Mycoplasma bovigenitalium strain PG11 T , Mycoplasma edwardii strain PG24 T , Mycoplasma maculosum strain Skotti B, Mycoplasma molare strain H542 T , Mycoplasma opalescens strain MH5408 T , and Mycoplasma spumans strain PG13T , representing other species that have been isolated from dogs (1), were obtained from The Mollicutes Collection. All strains were propagated under standard conditions (14) in ATCC 988 medium supplemented with fetal bovine serum (FBS) and glu...
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