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PubMed1997

Increasing resistance of Neisseria gonorrhoeae in west and central Africa. Consequence on therapy of gonococcal infection.

BACKGROUND AND OBJECTIVES: Antimicrobial resistant strains of Neisseria gonorrhoeae have spread with remarkable rapidity in many African countries. Chromosomal resistance to penicillin, tetracycline, and thiamphenicol is frequent now, and reported prevalences of penicillinase-producing N. gonorrhoeae isolates vary between 15% and 80%. Plasmid-mediated tetracycline-resistant N. gonorrhoeae isolates have been observed in several African countries. GOALS: To characterize gonococcal isolates from three sites in West and Central Africa, to determine antimicrobial susceptibility patterns, to document the spread of plasmid-mediated resistance to penicillin and tetracycline in these three sites, and to discuss the consequences of rising antimicrobial resistance on the management of gonococcal infection in Africa. STUDY DESIGN: Over time, a total of 2,288 gonococcal isolates were obtained from Abidjan, Ivory Coast (1992-1993, n = 251), from Kigali, Rwanda (1988-1993, n = 952), and from Kinshasa, Zaire (1988-1990, n = 1,085). The isolates were characterized by auxotyping and serotyping. Plasmid-mediated resistance to penicillin and to tetracycline was determined. Antimicrobial susceptibility testing to ceftriaxone, ciprofloxacin, penicillin, spectinomycin, tetracycline, and thiamphenicol was performed with an agar dilution method. RESULTS: The prevalence of penicillinase-producing N. gonorrhoeae increased significantly over time from 44% to 57% in Kigali and remained stable at a high level in Abidjan (73%) and in Kinshasa (67%). The frequency of tetracycline-resistant N. gonorrhoeae increased significantly during the observation periods in all three sites: from 20% to 65% in Abidjan, from 0% to 64% in Kigali, and from 14% to 41% in Kinshasa. Chromosomal resistance to penicillin was common in Kigali and Kinshasa, and chromosomal resistance to tetracycline and thiamphenicol was frequent in all three sites. All gonococcal isolates were susceptible to ceftriaxone, ciprofloxacin, and spectinomycin. Prototrophic and proline requiring strains were predominant, and IA-6 was the most common serovar in the three sites. IB-specific serovars were more common among penicillinase-producing N. gonorrhoeae and IA-specific serovars were more frequent among tetracycline-resistant N. gonorrhoeae, but there was no evidence for a clonal spread of resistant strains. CONCLUSIONS: This study illustrates the high frequency of resistant gonococci in Africa and shows that tetracycline-resistant N. gonorrhoeae have become highly endemic in different geographic areas of the continent. The use of effective drugs is essential to reduce gonorrhea transmission. Surveillance of temporal changes in antimicrobial resistance in gonococcal strain populations should be part of sexually transmitted diseases control programs.

Cote d'Ivoire↗
PubMed1997

Antimicrobial resistance in Neisseria gonorrhoeae in Finland, 1976 to 1995. The Finnish Study Group For Antimicrobial Resistance.

BACKGROUND AND OBJECTIVES: The worldwide increase in antimicrobial resistance in Neisseria gonorrhoeae prompted the authors to evaluate the status and course of resistance in gonococci in Finland. GOALS: The minimal inhibitory concentrations (MIC) of penicillin, tetracycline, spectinomycin, ciprofloxacin, ceftriaxone, and cefixime were tested for 337 consecutive clinical N. gonorrhoeae isolates collected in 19 Finnish microbiology laboratories in 1993. STUDY DESIGN: The results were compared with data obtained in three Finnish laboratories in 1986 and contrasted with the development of the incidence of gonorrhea and the prevalence of penicillinase-producing N. gonorrhoeae (PPNG) in Finland, 1976 to 1995. The number of strains with an elevated MIC to ciprofloxacin was assessed by questionnaire. RESULTS: A decrease, from more than 50% in 1986 to 20% in 1993, of strains susceptible to penicillin and tetracycline was observed. The prevalence of PPNG increased from 0% (1976) to 5.7% (1995). In 1995, two strains with a ciprofloxacin MIC of > or = 32 micrograms/ml were reported. No resistance to ceftriaxone or spectinomycin was detected. CONCLUSIONS: In spite of the rarity of gonorrhea and the availability of efficient antimicrobials in Finland, monitoring of the antimicrobial resistance of N. gonorrhoeae remains important.

Cephalosporins↗
PubMed2002

Surveillance of antibiotic resistance of Neisseria gonorrhoeae isolates in China, 1993-1998.

BACKGROUND: The prevalence of sexually transmitted diseases (STDs) has been increasing in China since the 1980s. Because gonorrhea is the most frequently reported STD there, information on the antimicrobial susceptibility of Neisseria gonorrhoeae will aid in its control. GOAL: To investigate the antimicrobial susceptibility of N gonorrhoeae isolates in China and to provide data for formulation of treatment guidelines and control policies. METHODS: The agar dilution technique was used to determine antimicrobial susceptibility, and acidimetric method was used to test for penicillinase-producing N gonorrhoeae. RESULTS: A total of 3186 gonococcal isolates were tested during the 6-year study period. The rate of resistance to penicillin was 66.70%; 8.14% of isolates were penicillinase-producing N gonorrhoeae. The percentage of tetracycline-resistant isolates was 92.03%, and that of highly tetracycline-resistant isolates was 4.65%. The rate of resistance to ciprofloxacin was also relatively high (34.25%). The rates of resistance to spectinomycin and ceftriaxone were 0.44% and 0.57%. CONCLUSIONS: The gonococcal isolates in China are relatively highly resistant to penicillin, tetracycline, and ciprofloxacin, but most of them are still susceptible to spectinomycin and ceftriaxone. Standardized treatment of gonorrhea is needed to prevent further spread of resistant gonococcal strains.

Adult↗
PubMed2002

In vitro susceptibility of 120 strains of Neisseria gonorrhoeae isolated in Kyrghyzstan.

BACKGROUND: The World Health Organization has established a worldwide program for gonococcal antimicrobial surveillance, but so far no data on gonococcal susceptibility in Central Asia are available. GOAL: The need for biological data on the susceptibility of Neisseria gonorrhoeae in Kyrghyzstan, to enable adaptation of the national treatment protocol for gonococcal infections, led Médecins Sans Frontières and Epicentre to conduct a survey in collaboration with the Alfred Fournier Institute in Paris and the health authorities in Bishkek. STUDY DESIGN: In vitro susceptibility of N gonorrhoeae strains was determined with use of the reference agar-plate dilution technique. RESULTS: Results for 11 antibiotics tested on 120 strains of gonococci showed a low proportion (11.7%) of penicillinase-producing N gonorrhoeae and high proportions of intermediate or resistant strains to the majority of the antibiotics tested, including fluoroquinolones (>or=25% of strains resistant). All the strains were susceptible to spectinomycin, and only two strains had decreased susceptibility to cefixime. CONCLUSION: The therapeutic choices available in Kyrghyzstan appear to be limited to cephalosporins and spectinomycin.

Anti-Bacterial Agents↗
PubMed2005

Antimicrobial resistance of Neisseria gonorrhoeae in selected World Health Organization Southeast Asia Region countries: an overview.

BACKGROUND AND OBJECTIVES: A Gonococcal Antimicrobial Susceptibility Program (GASP) under the World Health Organization South East Asia Region (WHO SEAR) is continuing in India and neighboring countries and is being coordinated by the WHO Regional Reference Laboratory (RRL), Vardhman Mahavir Medical College, and Safdarjung Hospital, New Delhi. GOAL: The present communication describes the current status and trends of antimicrobial resistance patterns of Neisseria gonorrhoeae, isolated in different focal-point laboratories under GASP, as presented in WHO SEAR intercountry consultative meeting conducted in December 2001. STUDY: Seven laboratories from India and 1 each from Bangladesh, Sri Lanka, and Nepal presented their data for the year 2000/2001. In addition, RRL Delhi, Bangladesh, and Sri Lanka presented data for the years 1995 to 2001, 1997 to 2001, and 1996 to 2000, respectively. Either National Committee for Clinical Laboratory Standards or calibrated dichotomous sensitivity technique was used in the different laboratories for determining antimicrobial susceptibility. RESULTS: It was observed that in the Indian laboratories, penicillin resistance varied from 20% to 79%, tetracycline resistance from 0% to 45.6%, and ciprofloxacin from 10.6% to 100%. Chromosomal, as well as plasmid-mediated resistance, was observed. The strains were reported to be less sensitive to ceftriaxone in 5 out of 7 laboratories, while none reported spectinomycin resistance. The reasons for wide variation in the results could be due to geographical strain difference in different parts of this vast country. At Sri Lanka, gonococci showed resistance towards penicillin (96.8%) and ciprofloxacin (8.2%). Bangladesh reported N. gonorrhoeae with ciprofloxacin (76%), penicillin (33%), and tetracycline (50%) resistance and decreased susceptibility to ceftriaxone (1.5%). Both the laboratories did not report any spectinomycin resistance. The resistance trends in these 2 centers and the RRL, New Delhi, showed different patterns. CONCLUSION: The report indicates the necessity for continuous surveillance of antimicrobial resistance pattern in this region of WHO for establishing antimicrobial policy guidelines for management of this common but important sexually transmitted infection (STI) pathogen, known to facilitate human immunodeficiency virus (HIV) infection. It also highlights the importance of ensuring quality assurance in the techniques in order to generate uniform data.

Anti-Bacterial Agents↗
PubMed1992

Aminoglycoside and aminocyclitol antibiotics: hygromycin B is an atypical bactericidal compound that exerts effects on cells of Escherichia coli characteristics for bacteriostatic aminocyclitols.

The effects of aminoglycoside and aminocyclitol antibiotics on intact cells of Escherichia coli were compared. The aminoglycosides streptomycin, gentamicin, kanamycin and neomycin had similar, but not identical, effects. They all caused misreading during protein synthesis, permeabilization of the cell membrane, inhibition of the initiation of DNA replication, and loss of cell viability. Cells treated with these antibiotics continued to synthesize two proteins (apparent molecular masses 72 and 60 kDa) that were not made by cells treated with the aminocyclitol hygromycin B, which did not cause misreading. Cells treated with the aminoglycosides regained their membrane tightness after residual protein synthesis in these cells had been inhibited by chloramphenicol, suggesting that under these conditions the mistranslated membrane proteins were rapidly degraded. The bacteriostatic aminocyclitols spectinomycin and kasugamycin did not cause membrane permeabilization, suggesting that these compounds do not cause misreading. Hygromycin B resembled these aminocyclitols in that it inhibited protein synthesis without causing misreading, membrane permeabilization or inhibition of initiation of DNA synthesis. However, hygromycin B also decreased cell viability. In minimal medium this lethal effect began late in comparison to the process of inhibition of protein synthesis. It is concluded that hygromycin B is an atypical bactericidal antibiotic that strongly resembles the bacteriostatic aminocyclitols spectinomycin and kasugamycin in its action.

Anti-Bacterial Agents↗
PubMed2003

Evaluation of selective media for the isolation of Brachyspira aalborgi from human faeces.

The purposes of this study were to identify a solid medium that supports improved growth of the anaerobic intestinal spirochaete Brachyspira aalborgi, to modify this for use as a selective isolation medium and then to test the medium for its effectiveness in isolating B. aalborgi from patients' faeces. Of the media evaluated, brain heart infusion agar (BHIA) with 10 % bovine blood (BB) was the most effective base-supplement combination for growth, with colonies attaining 1.2 mm in diameter by 21 days. Incubation in an anaerobic jar (94 % H(2), 6 % CO(2)) permitted growth of larger colonies than incubation in an anaerobic chamber (80 % N(2), 10 % H(2), 10 % CO(2)). Growth was improved only slightly at 38.5 degrees C compared with 37 degrees C. Selection of B. aalborgi from artificially seeded faeces was achieved equally well on eight different solid media containing spectinomycin (400 micro g ml(-1)) alone or in combinations with polymyxin B (5 micro g ml(-1)), colistin (25 micro g ml(-1)) and rifampicin (12.5 micro g ml(-1)). By using BHIA 10 % BB with spectinomycin plus polymyxin B, B. aalborgi was isolated from one of five human faecal samples that were positive for B. aalborgi by PCR amplification. This is the first report of the isolation of B. aalborgi from human faeces.

Culture Media↗
PubMed2005

Molecular characterization of a multidrug-resistant strain of enteroinvasive Escherichia coli O164 isolated in Japan.

Enteroinvasive Escherichia coli (EIEC) O164 strain RIMD05091045 was isolated from a travelling patient suffering from diarrhoea at the Osaka airport quarantine facility in Japan. The strain showed multidrug resistance against streptomycin, spectinomycin, co-trimoxazole (trimethoprim/sulfamethoxazole) and ampicillin, and reduced susceptibility to ciprofloxacin. Molecular characterization of the multidrug-resistance phenotype revealed the presence of a class 1 integron containing three genes, a dihydrofolate reductase type XII gene, dfrXII, which confers resistance to trimethoprim, an aminoglycoside adenyltransferase gene, aadA2, which confers resistance to streptomycin and spectinomycin, and an ORF of unknown function. Southern blot hybridization and conjugation experiments showed that the class 1 integron was located on a transferable plasmid that was less than 90 kb in size. The resistance of EIEC O164 to ampicillin was found to be due to the presence of TEM-1 beta-lactamase. On the other hand, a single mutation that has not previously been described, P158-to-S, was detected downstream of the quinolone-resistance-determining region of parC of topoisomerase IV and may be responsible for the reduced susceptibility to ciprofloxacin in this strain.

Ampicillin Resistance↗
PubMed2005

Genomic analysis of a multidrug-resistant strain of enterohaemorrhagic Escherichia coli O157:H7 causing a family outbreak in Japan.

A family outbreak of enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection occurred in October 2003 in the Hiroshima prefecture, Japan. Four isolates of EHEC O157:H7, 03064, 03065, 03066 and 03067, were recovered from a 1-year-old daughter, mother, father and 3-year-old daughter, respectively. All EHEC O157:H7 isolates were positive for Stx1 and Stx2 Shiga toxins. Surprisingly, DNA fingerprinting profiles obtained by PFGE showed that the first isolate, 03064, had unique XbaI and BlnI profiles that differed from the other three isolates. Also, plasmid analysis results revealed that isolate 03064 contained an extra plasmid larger than the classic large plasmid of EHEC O157, pO157 (93.6 kb). This new plasmid was named pMDR157. Furthermore, isolate 03064 showed a multidrug-resistance (MDR) phenotype against streptomycin, spectinomycin, co-trimoxazole (trimethoprim/sulfamethoxazole), ampicillin and tetracycline; the other isolates were completely sensitive to these antibiotics. Molecular analysis of the MDR phenotype in this unique strain revealed the presence of a class 1 integron containing two gene cassettes: a dihydrofolate reductase type 1 gene (dfrI), which confers resistance to trimethoprim, and an aminoglycoside adenyltransferase gene (aadA1), which confers resistance to streptomycin and spectinomycin. Southern blot hybridization showed that the class 1 integron was located in the extra plasmid, pMDR157. The ampicillin resistance was found to be due to the presence of the TEM-1-type beta-lactamase gene. The MDR phenotype was transferred successfully to E. coli HB101 by conjugation, indicating that both the class 1 integron and the TEM-1 beta-lactamase were located on the conjugative transferable plasmid, pMDR157. To the authors' knowledge, this is the first report of the identification of a beta-lactamase gene in EHEC O157.

Anti-Bacterial Agents↗
PubMed2006

Antimicrobial susceptibility of Neisseria gonorrhoeae isolated in Jiangsu Province, China, with a focus on fluoroquinolone resistance.

In this study, the phenotypic and genotypic resistance to fluoroquinolones in Neisseria gonorrhoeae isolated in Jiangsu Province, China, was analysed. In vitro susceptibility testing of eight antimicrobial agents, including ciprofloxacin and levofloxacin, against 95 clinical isolates was carried out. Detection of mutations in the gyrA and parC genes was performed by sequence analysis. The clinical isolates demonstrated 100% resistance to ciprofloxacin and 98.9% non-susceptibility to levofloxacin. All of the isolates were susceptible to cefotaxime and ceftriaxone. For cefepime, spectinomycin and tetracycline, 98.9, 94.7 and 1.1% of the isolates were susceptible, respectively. None of the isolates was susceptible to penicillin. Five types based on gyrA mutations could be categorized among 54 isolates with seven different mutation sites found on their parC gene. Analysis of sequence results showed that the gyrA mutation Asp-95-->Ala and the parC mutations Ser-87-->Arg and Ser-87-->Asn made a significant contribution to the resistance to fluoroquinolones, in addition to double mutations found in each gene. Therefore, the use of fluoroquinolones in the treatment of N. gonorrhoeae infections in Jiangsu Province is not recommended, while the use of third- and fourth-generation cephalosporins and spectinomycin is recommended.

Adult↗
PubMed1992

Long regions of homologous DNA are incorporated into the tobacco plastid genome by transformation.

We investigated the size of flanking DNA incorporated into the tobacco plastid genome alongside a selectable antibiotic resistance mutation. The results showed that integration of a long uninterrupted region of homologous DNA, rather than of small fragments as previously thought, is the more likely event in plastid transformation of land plants. Transforming plasmid pJS75 contains a 6.2-kb DNA fragment from the inverted repeat region of the tobacco plastid genome. A spectinomycin resistance mutation is encoded in the gene of the 16S rRNA and, 3.2 kb away, a streptomycin resistance mutation is encoded in exon II of the ribosomal protein gene rps12. Transplastomic lines were obtained after introduction of pJS75 DNA into leaf cells by the biolistic process and selection for the spectinomycin resistance marker. Homologous replacement of resident wild-type sequences resulted in integration of all, or almost all, of the 6.2-kb plastid DNA sequence from pJS75. Plasmid pJS75, which contains engineered cloning sites between two selectable markers, can be used as a plastid insertion vector.

Base Sequence↗
PubMed2005

Crystallization and preliminary crystallographic analysis of an aminoglycoside kinase from Legionella pneumophila.

9-Aminoglycoside phosphotransferase type Ia [APH(9)-Ia] is a resistance factor in Legionella pneuemophila, the causative agent of legionnaires' disease. It is responsible for providing intrinsic resistance to the antibiotic spectinomycin. APH(9)-Ia phosphorylates one of the hydroxyl moieties of spectinomycin in an ATP-dependent manner, abolishing the antibiotic properties of this drug. Here, the crystallization and preliminary X-ray studies of this enzyme in two crystal forms is reported. One of the these crystal forms provides diffraction data to a resolution of 1.7 A.

Bacterial Proteins↗
PubMed2004

Identification and characterization of class 1 integron resistance gene cassettes among Salmonella strains isolated from healthy humans in China.

Twenty-three strains of Salmonella spp. isolated from healthy humans in Guangdong, China, were examined for their susceptibility to ten common antibiotics and the presence of antibiotic resistance integrons. All the strains were resistant to at least one antibiotic, and 4 strains were positive for the intI1 gene. Polymerase chain reaction using in-F and in-B primers showed the existence of amplicons of 1,009 bp in two, 1,664 bp in one, and 1,009 bp and 1,664 bp in one of the intI1 -positive isolates, respectively. Sequence analysis revealed that the 1,009-bp amplicon harbored gene cassette aadA2, conferring resistance to spectinomycin, and the 1,664-bp amplicon harbored genes aadA5 and dfr17, conferring resistance to spectinomycin, streptomycin and trimethoprim. Meanwhile the experiments of plasmid conjugation and Southern hybridization with intI1 as the DNA probe indicated that all the integrons found in these strains were chromosomal. Because the strains carrying class 1 integrons were isolated from healthy humans, it suggests the need for all-round surveillance of the antibiotic resistance of pathogens.

Anti-Bacterial Agents↗
PubMed2006

Multidrug resistance and distribution of Salmonella serovars in slaughtered pigs.

The present study was undertaken to estimate the occurrence and distribution of multidrug resistance (MDR) among Salmonella serovars isolated from slaughtered pigs at Debre Zeit, Ethiopia. A total of 501 different samples were examined of which 42 (41.6%) of 101 mesenteric lymph nodes, 22 (21.8%) of 101 tongues, 17 (16.8%) of 101 caecal contents, 11 (11.1%) of 99 livers and two (2%) of 99 muscle (diaphragm and abdomen) samples were Salmonella positive. Of the 94 Salmonella isolates representing 15 different serovars, 69 (73.4%) were multidrug resistant (resistance to two or more antimicrobials). Among the Salmonella serovars a high level of MDR was observed in S. Hadar, S. Kentucky, S. Blockley and S. Enteritidis mainly to tetracycline (88.6%), streptomycin (82.9%), nitrofurantoin (74.3%), nalidixic acid and ciprofloxacin (42.9% each), sulfisoxazole (21.1%) and spectinomycin (20%). The pattern of MDR varied from two to eight antimicrobials among the resistant Salmonella serovars. The common profiles of resistance among the MDR serovars were the combined resistance to nitrofurantoin, streptomycin and tetracycline (R type NitStrTet, 51.4%), ciprofloxacin, nalidixic acid and nitrofurantoin (R type CipNalNit, 10%), ciprofloxacin, nalidixic acid, spectinomycin, streptomycin, sulfisoxazole and tetracycline (R type CipNalSptStrSulTet, 14.3%) and to ciprofloxacin, kanamycin, nalidixic acid, neomycin, nitrofurantoin, streptomycin and tetracycline (R type CipKanNalNeoNitStrTet, 10%). Results of the present study indicate the widespread occurrence and distribution of MDR Salmonella serovars in slaughtered pigs which could be a potential source of human MDR Salmonella infections.

Abattoirs↗
PubMed1986

Penicillinase-producing Neisseria gonorrhoea as a cause of neonatal and adult ophthalmia.

A retrospective analysis of 80 cases of gonococcal ophthalmia revealed six (7.5%) to be due to penicillinase-producing Neisseria gonorrhoeae (PPNG), five neonatal cases and one adult. All six cases were finally cured, but best results were obtained with topical chloramphenicol and single-dose spectinomycin (40 mg/kg) given intramuscularly. All gonococcal isolates should be tested promptly for penicillinase production, and if this is present systemic treatment, modified to spectinomycin or penicillinase-stable cephalosporin, should be given as single-dose treatment.

Adult↗
PubMed1977

Pelvic tissue and serum concentrations of various antibiotics given as pre-operative medication.

Talampicillin, cephalexin and clindamycin were administered orally, and ampicillin, cephazolin, clindamycin and spectinomycin intramuscularly as preoperative medication to 49 women who were having an abdominal hysterectomy. Antibiotic levels in serum, myometrium or cervix, and Fallopian tube were estimated. Antibiotic absorption from the gastrointestinal tract was delayed, but intramuscular therapy produced serum levels compatible with those reported in ambulant volunteers. None of the antibiotics produced a concentration which inhibited all the potential pathogens causing pelvic inflammatory disease. Inhibitory concentrations were produced by cephazolin except against Bacteroides; by clindamycin except against enterobacteria; by ampicillin except against Bacteroides and enterobacteria; and by spectinomycin except against resistant strains of streptococci. The need for a reassessment of dose regimens and route of administration as well as the possible need for using two antibiotics together for the treatment of pelvic inflammatory disease is suggested.

Anti-Bacterial Agents↗
PubMed2000

Characterisation of two new gene cassettes, aadA5 and dfrA17.

Escherichia coli INS33 was isolated from the urinary tract of an infected patient. It was resistant to ampicillin, chloramphenicol, spectinomycin, streptomycin, sulfafurazole, tetracycline and trimethoprim. PCR screening revealed the presence of a class 1 integron that harboured two new gene cassettes, designated dfrA17 and aadA5. The new dfrA17 cassette was 91% identical to the known dfrA7 cassette. The aadA5 cassette was 95% identical over the first 830 bp to aadA4, but lacked the IS26 element found at the 3' end of this truncated cassette. Cloning and expression of the cassette region demonstrated that dfrA17 conferred high level resistance to trimethoprim but aadA5 conferred resistance to spectinomycin but not to streptomycin.

Amino Acid Sequence↗
PubMed1977

Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria.

Several mutants of Escherichia coli affecting aerobic energy generation and energization of the bacterial membrane have been examined for their effect on streptomycin and gentamicin accumulation and susceptibility. A heme-deficient mutant (K207) and two mutants (CJ-8 [colicin K insensitive] and NR-70) associated with defective aerobic active transport were associated with decreased transport of streptomycin and gentamicin and increased resistance to those antibiotics. These mutants also exhibited increased resistance to several other aminoglycoside antibiotics, but not the aminocyclitol spectinomycin. The same observations were made with a ubiquinone-deficient mutant, but a strA derivative of this mutant was shown additionally to be saturable for streptomycin accumulation at a concentration four or more times lower than that required for saturation of the parent. A mutant uncoupled for adenosine 5'-triphosphate synthesis from electron transport and membrane Mg-adenosine 5'-triphosphatase deficient was hypersensitive to those aminoglycosides tested and spectinomycin, and showed enhanced transport of streptomycin and gentamicin. A variety of compounds structurally related to streptomycin were examined at high concentrations for inhibition of streptomycin uptake in a strA mutant of E. coli K-12 SA 1306, but no evidence for competition was detected, suggesting the absence of a common transport carrier. Four different divalent cations were shown to inhibit streptomycin and gentamicin accumulation in E. coli K-12 SA 1306. Divalent cations were shown to inhibit uptake of these two drugs in two bacterial species with distinct cell wall structures, Pseudomonas aeruginosa and Staphylococcus aureus, and to inhibit streptomycin uptake in spheroplasts of streptomycin-susceptible and -resistant E. coli. However, calcium had almost no inhibitory effect on streptomycin uptake by the ubiquinone-deficient mutant E. coli AN66. These and previous findings have been used to formulate a model for aminoglycoside entry into bacteria using a low-affinity membranous complex involved in membrane energization that includes respiratory quinones, which probably act to bind and transport aminoglycosides across the cell membrane. This phase of transport is associated with the lowest accumulation rate (termed energy-dependent phase I) that is rate limiting for susceptibility. It is further proposed that subsequent association of the membrane-bound aminoglycoside with higher-affinity binding sites on membrane-associated ribosomes carrying out a normal ribosomal cycle and protein synthesis results in a more rapid transport rate (termed energy-dependent phase II). The increased rate could result from a state of membrane energization analogous to that causing enhanced aminoglycoside transport rates seen in the uncoupled mutant, AN120. How this model explains the mechanism by which enzymatically modified aminoglycosides render cells resistant to unmodified aminoglycosides is also discussed.

Adenosine Triphosphatases↗