Streptococcal Infection In Mice Research Articles

Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine.

Group A streptococcus (GAS) is among the top 10 causes of mortality from an infectious disease, producing mild to invasive life-threatening manifestations. Necrotizing fasciitis (NF) is characterized by a rapid GAS spread into fascial planes followed by extensive tissue destruction. Despite prompt treatments of antibiotic administration and tissue debridement, mortality from NF is still high. Moreover, there is no effective vaccine against GAS, and early diagnosis of NF is problematic because its clinical presentations are not specific. Thus, there is a genuine need for effective treatments against GAS NF. Previously, we reported that GAS induces endoplasmic reticulum (ER) stress to gain asparagine from the host. Here, we demonstrate that GAS-mediated asparagine induction and release occur through the PERK-eIF2α-ATF4 branch of the unfolded protein response. Inhibitors of PERK or integrated stress response (ISR) blocked the formation and release of asparagine by infected mammalian cells, and exogenously added asparagine overcame this inhibition. Moreover, in a murine model of NF, we show that the inhibitors minimized mortality when mice were challenged with a lethal dose of GAS and reduced bacterial counts and lesion size when mice were challenged with a sublethal dose. Immunohistopathology studies demonstrated that PERK/ISR inhibitors protected mice by enabling neutrophil infiltration into GAS-infected fascia and reducing the pro-inflammatory response that causes tissue damage. Inhibitor treatment was also effective in mice when started at 12 hours after infection. We conclude that host metabolic alteration induced by PERK or ISR inhibitors is a promising therapeutic strategy to treat highly invasive GAS infections.

Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice

Severe invasive group A Streptococcus (GAS) infection evades anti-bacterial immunity by attenuating the cellular components of innate immune responses. However, this loss of protection is compensated for by interferon (IFN)-γ-producing immature myeloid cells (γIMCs), which are selectively recruited upon severe invasive GAS infection in mice. Here, we demonstrate that γIMCs provide this IFN-γ-mediated protection by sequentially sensing GAS through two distinct pattern recognition receptors. Ina mouse model, GAS is initially recognized by Toll-like receptor 2 (TLR2), which promptly induces interleukin (IL)-6 production in γIMCs. γIMC-derived IL-6 promotes the upregulation of a recently identified GAS-sensing receptor, macrophage-inducible C-type lectin (Mincle), in an autocrine or paracrine manner. Notably, blockade of γIMC-derived IL-6 abrogates Mincle expression, downstream IFN-γ production, and γIMC-mediated protection against severe invasive GAS infection. Thus, γIMCs regulate host protective immunity against severe invasive GAS infection via a TLR2-IL-6-Mincle axis.

Antibacterial molecule may discourage resistance

A new small molecule attacks bacteria by a mechanism that microbes could struggle to develop resistance against, according to a study. The compound, the study’s authors say, could lead to an antibiotic for drug-resistant bacteria. Richard H. Ebright of Rutgers University and coworkers, including scientists at the drug discovery company Naicons, found the agent, pseudouridimycin, by screening for extracts from soil microbes that inhibit bacterial RNA polymerase selectively (Cell 2017, DOI: 10.1016/j.cell.2017.05.042). The molecule blocks the active site of bacterial RNA polymerase by mimicking the structure of nucleoside triphosphates, which the enzyme uses to stitch together RNA. By preventing the nucleoside triphosphates from binding the enzyme, the agent shuts down RNA synthesis, killing the microbes. Pseudouridimycin killed different types of bacteria, including drug-resistant strains, in test tubes and cleared a streptococcal infection in mice. The study is “beautiful work” that could “actually lead t...

Sulfonamides in dermatology

The first sulfonamide therapy was discovered by Domagk, who, in 1932, discovered that an orange-red sulfonamide dye named prontosil rubrum was safe and effective in curing streptococcal infections in mice. He confirmed the effectiveness of the dye through various experiments The discovery of the sulfonamides represented the first real breakthrough in selective antimicrobial therapy. The sulfonamides (Fig 1) are synthetic bacteriostatic antimicrobials with a wide spectrum against most Gram-positive and many Gram-negative organisms. The widespread use of sulfonamides as a result of their low cost has resulted in the development of many sulfonamide-resistant strains of bacteria. In general, the sulfonamides exert only a bacteristatic effect, and cellular and humoral defense mechanisms of the host are essential for the final eradication of the infection. The earliest report on the use of sulfapyridine in a noninfectious dermatologic disease was in 1939, when it was used to treat a patient with acrodermatitis of Hallopeau. 1 The age of antibacterial chemotherapy started in 1935 when Gerhard Domagk published his successful application of “Prontosil rubrum” in animals and humans to fight streptococcal infections. The chemical agent was the azo dye sulfachrysoidine. Shortly thereafter, it was shown by another European group that this dye is metabolized to the therapeutically active, colorless sulfanilamide. 2 Various chemical modifications of this parent sulfonamide compound yielded a great number of sulfonamides with a relatively constant antibacterial spectrum yet with a widely varying number of pharmacokinetic and toxicological properties. In the beginning, sulfonamides were grouped according to their half-time of elimination. Today, we distinguish middle- and long-acting and poorly absorbed sulfonamides. Typical middle-acting sulfonamides are sulfadiazine and sulfamethoxazole, and long-acting ones are sulfalene and sulfadoxine.

Lysobactin, a novel antibacterial agent produced by Lysobacter sp. II. Biological properties.

Lysobactin, an antibiotic isolated from a strain of Lysobacter, is 2 to 4-fold more active than vancomycin against aerobic and anaerobic Gram-positive bacteria. Included in the spectrum of lysobactin are Staphylococci, Streptococci, corynebacteria, clostridia and various other Gram-positive anaerobic bacteria. The activity of lysobactin against aerobic and anaerobic Gram-negative bacteria is poor. When given parenterally the compound was efficacious in systemic staphylococcal and streptococcal infections in mice. Similarly, when applied topically lysobactin was also curative in a staphylococcal wound infection in mice. Some studies on the mode of action of lysobactin are presented.

Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721.

DuP 721 (p-acetylphenyloxooxazolidinylmethylacetamide) and DuP 105 (a methylsulfinyl derivative) are orally active representatives of the oxazolidinones, a new class of synthetic antibacterial agents. Their antibacterial spectrum includes staphylococci, streptococci, and Bacteroides fragilis strains. The compounds have equal activity against staphylococcal strains susceptible or resistant to beta-lactam antibiotics, including methicillin-resistant strains. The MICs for 90% of the strains (MIC90s) against staphylococcal isolates were 1 to 4 micrograms/ml for DuP 721 and 4 to 16 micrograms/ml for DuP 105, compared with 1 to 2 micrograms/ml for vancomycin, 0.5 microgram/ml for ciprofloxacin, and 2 to greater than 16 micrograms/ml for imipenem. The MIC90s against group D streptococci were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 2 micrograms/ml for vancomycin, ciprofloxacin, and imipenem. MIC90s against B. fragilis isolates were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 8 micrograms/ml for cefoxitin. DuP 721 and DuP 105 administered by either the oral or the parenteral route were protective against staphylococcal and streptococcal infections in mice. The 50% effective doses were 2 to 10 mg/kg for DuP 721, 9 to 23 mg/kg for DuP 105, and 2 to 12 mg/kg for vancomycin. These results indicate that further studies of compounds of the oxazolidinone series are warranted.

The influence of different stages of pregnancy on group B streptococcal infection in mice

Eight-day pregnant mice were found to be more resistant to the lethal effects of group B streptococci than those which were 17 days pregnant. From studies on the multiplication of the organisms in vivo it is suggested that the apparent enhancement of the infection in the 17-day pregnant animals is due to the lethal effects of the greater number of streptococci found in their tissues.

Type III group B streptococcal infections in mice: bacteremia and meningitis following oral inoculation

The successful production of disease in mice by a type III group B streptococcus is described in this report. When injected intravenously, 106 organisms produced a fulminating sepsis and resulted in 100% mortality within 48 h. Inoculation of 108 - 109 organisms directly onto the surface of the oropharynx progressed to bacteremia and meningitis in greater than 50% of animals. In a group of mice treated with penicillin immediately after oropharyngeal inoculation, the incidence of invasive bacteremia was reduced to 30%. The use of this animal model for studying the pathogenesis and treatment of experimentally produced meningitis and eradication of oropharyngeal colonization is discussed.

Experimental group B streptococcal infections in mice: hematogenous virulence and mucosal colonization.

A group B streptococcus recovered from a blood specimen from a neonate with sepsis was used to evaluate the use of mice for studies characterizing the hematogenous virulence and the asymptomatic mucosal colonization of the vagina or of the respiratory tract by these bacteria. When injected intravenously, the 50% lethal dose for mice was 10(6); however, as few as 10(2) organisms produced septic deaths. In mice undergoing water diuresis, bacteriuria and pyelonephritis were not produced after direct bladder inoculation of the streptococci. Asymptomatic vaginal colonizations that persisted for 12 days were produced in both pregnant and virgin mice. Vaginal colonization before delivery did not result in transmission of infection to litters or in protection against subsequent oropharyngeal colonization in the suckling mice. In mice born of nonexposed mothers, oropharyngeal colonization was produced in both suckling and 3-week-old weaned mice. Whereas infection persisted for 14 days in all suckling mice, clearance occurred in over 50% of the weaned mice by day 14. The use of mice for studies on the virulence of the group B streptococci as well as for studies on the pathogenesis of disease by virulent strains is discussed.

Protective action of estrogen against streptococcal infection in mice, and its relation to connective tissue.

Protective action of estrogen against streptococcal infection in mice, and its relation to connective tissue.

Antibacterial Activity of a Series of Diphenylmethanes

Thirty-eight derivatives of diphenylmethane were examined for antibacterial activity against a variety of organisms. Activity in vitro appeared more or less specific for Gram-positive bacteria, twenty-three derivatives being bactericidal for this type in concentrations ranging from 0.004 to 4.0mg. per cent, while only seven compounds were active against the respective Gram-negative organisms at levels of 0.5 to 4.0mg. per cent. Activity of the diphenylmethanes seemed to be dependent upon both hydroxy and halogen grou substitution in the parent structure, the position of these groups being of considrable importance. Substitution of various other groupings are discussed in an attempt to correlate chemical structure with activity. Antibacterial properties of the diphenylmethanes were markedly reduced in the presence of serum. Although the majority of compounds in the present series were found highly bactericidal for streptococci, none of the derivatives tested showed any marked protective action against experimental streptococcal infection in mice.

Experimental approach to the problem of treatment failure with penicillin: I. Group a streptococcal infection in mice

In an experimental infection of mice with group A beta-hemolytic streptococci the organisms at the site of inoculation remained highly sensitive to the bactericidal action of the drug only as long as they continued to multiply at a rapid rate. When the bacterial population in the muscle focus approached a plateau value, they simultaneously became refractory to the drug and it required days to effect sterilization and cure, instead of as many hours. The refractory state of the organisms was not due simply to the large number of organisms present in the older infection, and there was no evidence that a systemic host factor had been impaired. Further, massive doses of aqueous penicillin which provided concentrations in the muscle 10, 000 times greater than the minimal effective concentration were no more effective than the relatively low concentrations afforded by an injection of procaine penicillin in oil gelled with aluminum monostearate. The proposed explanation for the refractory state of the organisms in the older infection is that in such foci the organisms were no longer multiplying and metabolizing as actively as in the fresh infection, due either to the inadequate diffusion of metabolites into the area of infection or to the local release of toxic products. Possible implications with respect of the therapeutic use of penicillin in man are discussed in the text.

Lack of interference of chloramphenicol with penicillin in a hemolytic streptococcal infection in mice.

Summary1. Mice were infected with group A streptococci and treated with chloramphenicol and penicillin, separately and in combination. Jawetz's observation that chloramphenicol interfered with penicillin when animals were given a single aqueous injection of both antibiotics was confirmed. 2. The interference was not demonstrable, however, when antibiotic blood levels were maintained for 2 or 3 days. Thus, despite early interference, the combination caused a progressive bactericidal action which, in conjunction with phagocytosis, protected the mice as well as penicillin alone. 3. These experiments imply that the phenomenon of antibiotic interference is seldom of clinical significance.

Effect of Sanguinin, an antibacterial agent from blood, on streptococcal infection in mice.

Summary and ConclusionsThe blood hydrolysate Sanguinin was tested in vivo in 268 albino mice accompanied by 221 untreated controls for its effectiveness against the beta-hemolytic Streptococcus zooepidemicus. Sanguinin solution (20 mg/ml) was inoculated subcutaneously (0.25 to 1.0 mg/mouse daily, usually for 4-6 days) either prior or after infection. Suppressive effect on the course of the infection was noted in all series of treated mice. A significant increase in survival time was noted in the pretreated series with an average survival percentage of 38.9 compared with 6.0 of the total of untreated controls. It does not appear that a direct correlation can be established between the survival rates and the intake of Sanguinin or the length of its administration, however, pretreatment seems to be of decisive value.

NEW DEVELOPMENTS IN THE MANAGEMENT OF LEPROSY

Editorial1 March 1949NEW DEVELOPMENTS IN THE MANAGEMENT OF LEPROSYH. J. L. M.H. J. L. M.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-30-3-692 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Excerpt"Glider, parachute, submarine rescue, experimental diving,handling of lepers, demolition of explosives, observation flying." These categories were recommended for "Hazard Pay" by the Advisory Committee on Service Pay as recently as December 1948. When the justification for listing the demolition of explosives and the handling of lepers as comparable hazards was challenged, a spokesman of the committee defended the inclusion of leper handling on the grounds that hazard pay would compensate for "the fear of the disease felt by the average individual and the social stigma attendant to such service." This attitude is both an anachronism and a disgrace. As...1 MCCOY GW: Factors in public health management of leprosy, Pub. Health Rep., 1948, lxiii, 1522. CrossrefGoogle Scholar2 ROGERS L: Progress in the control of leprosy in the British Empire, British Med. Jr., 1946, i, 825. CrossrefGoogle Scholar3 AUSTIN CJ: Correspondence, British Med. Jr., 1947, i, 506. CrossrefGoogle Scholar4 GRAY H: The chemotherapy of leprosy, New Orleans Med. and Surg. Jr., 1947, c, 218. Google Scholar5 International Leprosy Congress Report 1938, Internat. Jr. Leprosy, 1938, vi, 408. Google Scholar6 GOODMANGILMAN LA: The Pharmacological Basis of Therapeutics, 1941, The Macmillan Co., N. Y., p. 944. Google Scholar7 MCCOY GW: Chaulmoogra oil in treatment of leprosy, Pub. Health Rep., 1942, lvii, 1727. CrossrefGoogle Scholar8 REHFUSSALBRECHTPRICE MEFKAH: A Course in Practical Therapeutics, 1948, The Williams & Wilkins Co., Baltimore, p. 529. Google Scholar9 FITE GL: Leprosy, its detection and management, Postgraduate Med., 1947, i, 292. CrossrefGoogle Scholar10 SCHUJMAN S: Therapeutic value of chaulmoogra in the treatment of leprosy, Internat. Jr. Leprosy, 1947, xv, 135. Google Scholar11 COCHRANE RG: A comparison of sulphone and hydnocarpus therapy of leprosy, Internat. Jr. Leprosy, 1948, xvi, 139. Google Scholar12 International Leprosy Congress Report, 1948, Internat. Jr. Leprosy, 1948, xvi, 209. Google Scholar13 SCHUJMAN S: Comparative study of chaulmoogra in high doses and promin in the treatment of leprosy, Internat. Jr. Leprosy, 1948, xvi, 145. Google Scholar14 FROMMWITTMANN EJ: Derivate des p-nitrophenols, Ber. d. deutsch. chem. Gesellsch., 1908, xli, 2264. CrossrefGoogle Scholar15 BUTTLE GA: Treatment of streptococcal infections in mice with 4-4′-diaminodiphenylsulphone, Lancet, 1937, i, 1331. CrossrefGoogle Scholar16 FELDMAN WH: The treatment of experimental tuberculosis with promin; a preliminary report, Proc. Staff. Meet. Mayo Clin., 1941, xvi, 187. Google Scholar17 COWDRYRUANGSIRI EVC: Influence of promin, starch and hepatalhyde on experimental leprosy in rats, Arch. Path., 1941, xxxii, 632. Google Scholar18 FAGET GH: The promin treatment of leprosy: a progress report, Pub. Health Rep., 1943, lviii, 1729. CrossrefGoogle Scholar19 MUIR E: Preliminary report on diasone in treatment of leprosy, Internat. Jr. Leprosy, 1944, xii, 1. Google Scholar20 FAGET GH: The action of diasone in the treatment of leprosy, preliminary report, Internat. Jr. Leprosy, 1946, xiv, 19. Google Scholar21 FAGETERICKSON GHPT: Chemotherapy of leprosy, Jr. Am. Med. Assoc., 1948, cxxxvi, 451. CrossrefGoogle Scholar22 LIMA LD: Present status of sulfone therapy at the Padre Bento Sanatorium, Internat. Jr. Leprosy, 1948, xvi, 127. Google Scholar23 SLOAN NR: Effect of sulfone treatment on the larynx in leprosy, Internat. Jr. Leprosy, 1948, xvi, 329. Google Scholar24 JOHNSON HM: Discussion following Faget and Erickson's paper.21 Google Scholar25 COCHRANE RG: Correspondence, Brit. Med. Jr., 1947, ii, 110. CrossrefGoogle Scholar26 HINGSON RA: Preliminary study of the hypospray for parenteral therapy in its relation to the management of leprosy, Internat. Jr. Leprosy, 1948, xvi, 173. Google Scholar27 MOM M: Benadryl in lepra reaction of lepromatous leprosy and in sulfone sensitization, Rev. argent. dermatosif., 1947, xxxi, No. 2. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPulp death in a patient with lepromatous leprosyLepra 1 March 1949Volume 30, Issue 3Page: 692-700KeywordsFearLeprosy ePublished: 1 December 2008 Issue Published: 1 March 1949 PDF downloadLoading ...

Therapeutic Effectiveness of Single and Divided Doses of Penicillin in a Streptococcal Infection in Mice

ConclusionFrom 4 to 8 times as much penicillin was needed for oral, as for subcutaneous administration, to obtain the same degree of therapeutic effect in a streptococcal infection in mice.In this infection, the administration of daily penicillin dosage in a series of small equally spaced doses was not more effective than giving an equivalent amount of drug in 1 or 2 doses per day.

Chemotherapeutic Action of Various Forms of Penicillin on Hemolytic Streptococcal Infections in Mice.

SummaryThe comparative efficacy of 4 forms of penicillin and random samples of “commercial” penicillin has been studied in experimentally-produced hemolytic streptococcal infections in mice. On a unitage basis the relative chemotherapeutic efficacy of penicillin X, G, F and K under the experimental conditions used, was on the order of 500, 100, slightly less than 100, and 60 respectively. On a gravimetric basis, the relative order of efficacy was 270 for X, 100 for G, slightly less than 92 for F and 82 for K. The values for penicillin F were obtained with a preparation which contained impurities, the action of which is not known.All of the samples of “commercial” penicillin were 3 to 5 times as effective as crystalline penicillin G in protecting the animals against the infection. Moreover, the protective action exerted by these impure penicillins was of the same order regardless of the unitage per mg or the value of the Bacillus subtilis-Staphylococcus aureus differential ratio. The protective power of pu...

Therapeutic Effectiveness of Single Oral Doses of Penicillin

Survival of 97% was obtained a streptococcal infection in mice with penicillin powder containing 650 units per mg, administered in a single oral dose of mp per kilo.

Bacitracin: A New Antibiotic Produced by a Member of the B. subtilis Group

A new antibiotic "bacitracin" has been recovered from a strain of the B. subtilis group of organisms. It is neutral, water-soluble, non-toxic and relatively heat stable. In vitro it is active chiefly against Grampositive organisms, but the gonococcus and meningococcus are susceptible to its action. It is also active in vivo against experimentally produced hemolytic streptococcal infections in mice and gas gangrene infections in guinea pigs. Clinical use in hemolytic streptococcal and staphylococcal infections in man have given encouraging results.

SULFONAMIDE COMPOUNDS AND PENICILLIN

Penicillin and one of the sulfonamide compounds are frequently used simultaneously in treatment of serious infections in an attempt to enhance the therapeutic effect. Ungar, 1 in 1943, reported that sulfapyridine potentiated the action of penicillin, both in vitro and in a limited number of infected mice. Soo-Hoo and Schnitzer 2 confirmed Ungar's claim that penicillin and various sulfonamide drugs were synergistic in combatting streptococcic infections in mice. They also showed that penicillin could prevent the inhibiting action of paraaminobenzoic acid on the sulfonamide drugs. This observation suggested that, although penicillin and the sulfonamide drugs are presumed to act by different mechanisms, the combined effect might be greater than a summation and might represent a potentiation due to the inhibition by penicillin of the action of paraaminobenzoic acid present in pus and exudates and even in normal tissue fluids. T'ung 3 studied the in vitro effects of sodium sulfathiazole and