Mendrick, Donna (Gaithersburg, MD, US)
Porter, Mark (Gaithersburg, MD, US)
Johnson, Kory (Gaithersburg, MD, US)
Higgs, Brandon (Gaithersburg, MD, US)
Castle, Arthur (Gaithersburg, MD, US)
Elashoff, Michael (Gaithersburg, MD, US)

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08/19/2008

05/22/2002

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Ocimum Biosolutions, Inc. (Indianapolis, IN, US)

702/19

700/30, 435/6, 707/104.1, 702/22

G06F19/00

702/19, 700/30, 435/6, 707/104.1, 702/22

5811231	Methods and kits for eukaryotic gene profiling	September, 1998	Farr et al.	435/6
5858659	Polymorphism detection	January, 1999	Sapolsky et al.
5953727	Project-based full-length biomolecular sequence database	September, 1999	Maslyn et al.	707/104
5965352	Methods for identifying pathways of drug action	October, 1999	Stoughton et al.	435/4
6132969	Methods for testing biological network models	October, 2000	Stoughton et al.
6153421	Cloned genomes of infectious hepatitis C viruses and uses thereof	November, 2000	Yanagi et al.
6160105	Monitoring toxicological responses	December, 2000	Cunningham et al.	536/23.1
6185561	Method and apparatus for providing and expression data mining database	February, 2001	Balaban et al.	707/6
6203987	Methods for using co-regulated genesets to enhance detection and classification of gene expression patterns	March, 2001	Friend et al.	435/6
6218122	Methods of monitoring disease states and therapies using gene expression profiles	April, 2001	Friend et al.	435/6
6228589	Measurement of gene expression profiles in toxicity determination	May, 2001	Brenner	435/6
6229911	Method and apparatus for providing a bioinformatics database	May, 2001	Balaban et al.	382/128
6365352	Process to study changes in gene expression in granulocytic cells	April, 2002	Yerramilli et al.	435/6
6372431	Mammalian toxicological response markers	April, 2002	Cunningham et al.	435/6
6403778	Toxicological response markers	June, 2002	Cunningham et al.	536/22.1
6421612	System, method and computer program product for identifying chemical compounds having desired properties	July, 2002	Agrafiotis et al.
6461807	Methods for drug target screening	October, 2002	Friend et al.
20010039006	Toxicity typing using embryoid bodies	November, 2001	Snodgrass
20010049139	Hepatic regeneration from hematopoietic stem cells	December, 2001	Lagasse et al.
20020119462	Molecular toxicology modeling	August, 2002	Mendrick et al.
20020142284	Methods of identifying renal protective factors	October, 2002	Raha et al.	435/4
20030028327	Systems and methods for monitoring behavior informatics	February, 2003	Brunner et al.
20030124552	Biochips and method of screening using drug induced gene and protein expression profiling	July, 2003	Lindemann et al.
20030154032	Methods and compositions for diagnosing and treating rheumatoid arthritis	August, 2003	Pittman et al.

WO/1993/001205	January, 1993			TYROSINE KINASE
WO/1994/017208	April, 1994			METHODS AND DIAGNOSTIC KITS UTILIZING MAMMALIAN STRESS PROMOTERS TO DETERMINE TOXICITY OF A COMPOUND
WO/1995/011755	May, 1995			MICROFABRICATED, FLOWTHROUGH POROUS APPARATUS FOR DISCRETE DETECTION OF BINDING REACTIONS
WO/1997/013877	April, 1997			MEASUREMENT OF GENE EXPRESSION PROFILES IN TOXICITY DETERMINATION
WO/1997/016732	May, 1997			A PROCESS FOR IN VITRO ANALYSIS OF TOXIC AND ALLERGENIC SUBSTANCES
WO/1999/012118	March, 1999			COMPOUND SCREENING SYSTEM
WO/1999/027090	June, 1999			METHODS FOR IDENTIFYING THE TOXIC/PATHOLOGIC EFFECT OF ENVIRONMENTAL STIMULI ON GENE TRANSCRIPTION
WO/1999/032660	July, 1999			EXPLOITING GENOMICS IN THE SEARCH FOR NEW DRUGS
WO/1999/043345	September, 1999			AMINO ACID DEGRADING ENZYMES MODULATE CELL DEATH
WO/1999/058670	November, 1999			AGS PROTEINS AND NUCLEIC ACID MOLECULES AND USES THEREFOR
WO/2000/012760	March, 2000			TOXICOLOGICAL RESPONSE MARKERS
WO/2000/028092	May, 2000			METHOD FOR GENERATING GENE EXPRESSION PROFILES
WO/2000/039336	July, 2000			METHODS OF CHARACTERIZING DRUG ACTIVITIES USING CONSENSUS PROFILES
WO/2000/047761	August, 2000			HIGH-THROUGHPUT TOXICOLOGICAL TESTING USING CULTURED ORGANISMS AND CELLS
WO/2000/063435	October, 2000			METHOD OF IDENTIFYING TOXIC AGENTS USING DIFFERENTIAL GENE EXPRESSION
WO/2001/002609	January, 2001			METHOD OF IDENTIFYING TOXIC AGENTS USING DIFFERENTIAL GENE EXPRESSION
WO/2001/011076	February, 2001			IN VIVO HIGH THROUGHPUT TOXICOLOGY SCREENING METHOD
WO/2001/014425	March, 2001			MULTIPURPOSE DIAGNOSTIC SYSTEMS USING PROTEIN CHIPS
WO/2001/020043	March, 2001			METHOD OF CLUSTER ANALYSIS OF GENE EXPRESSION PROFILES
WO/2001/023886	April, 2001			IMPROVED TOXICITY SCREENING METHOD
WO/2001/025473	April, 2001			SYSTEMS AND METHODS FOR CHARACTERIZING A BIOLOGICAL CONDITION OR AGENT USING CALIBRATED GENE EXPRESSION PROFILES
WO/2001/032928	May, 2001			METHODS OF DETERMINING INDIVIDUAL HYPERSENSITIVITY TO AN AGENT
WO/2001/036684	May, 2001			MAMMALIAN TOXICOLOGICAL RESPONSE MARKERS
WO/2001/038579	May, 2001			METHOD OF IDENTIFYING TOXIC AGENTS USING NSAID-INDUCED DIFFERENTIAL GENE EXPRESSION IN LIVER
WO/2001/044512	June, 2001			METHOD OF IDENTIFYING LIGANDS FOR THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA USING DIFFERENTIAL GENE EXPRESSION
WO/2001/063279	August, 2001			METHOD OF IDENTIFYING TOXIC AGENTS USING DIFFERENTIAL GENE EXPRESSION
WO/2002/031704	April, 2002			INTERACTIVE CORRELATION OF COMPOUND INFORMATION AND GENOMIC INFORMATION
WO/2003/085083	October, 2003			LIVER NECROSIS PREDICTIVE GENES
WO/2003/095624	November, 2003			LIVER INFLAMMATION PREDICTIVE GENES
WO/2003/100030	December, 2003			KIDNEY TOXICITY PREDICTIVE GENES

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Smith, Carolyn L.

Cooley Godward Kronish LLP

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Applications 60/292,335 filed on May 22, 2001; 60/297,523 filed on Jun. 13, 2001; 60/298,925 filed on Jun. 19, 2001; 60/303,810 filed on Jul. 10, 2001; 60/303,807 filed on Jul. 10, 2001; 60/303,808 filed on Jul. 10, 2001; 60/315,047 filed on Aug. 28, 2001; 60/324,928 filed on Sep. 27, 2001; 60/330,867 filed on Nov. 1, 2001; 60/330,462 filed on Oct. 22, 2001; 60/331,805 filed on Nov. 21, 2001; 60/336,144 filed on Dec. 6, 2001; 60/340,873 filed on Dec. 19, 2001; 60/357,843 filed on Feb. 21, 2002; 60/357,842 filed on Feb. 21, 2002; 60/357,844 filed on Feb. 21, 2002; 60/364,134 filed on Mar. 15, 2002; 60/370,206 filed on Apr. 8, 2002; 60/370,247 filed on Apr. 8, 2002; 60/370,144 filed on Apr. 8, 2002; 60/371,679 filed on Apr. 12, 2002; and 60/372,794 filed on Apr. 17, 2002, all of which are herein incorporated by reference in their entirety. This application is also related to U.S. application Ser. Nos. 09/917,800 and 10/060,087, both of which are also herein incorporated by reference in their entirety.

We claim:

1. A method for determining whether a test compound is a renal toxin, comprising: (a) exposing kidney tissue or kidney cells to the test compound; (b) preparing a normalized gene expression profile of at least ten genes for said kidney tissue or kidney cells, wherein the gene expression profile contains the differential gene expression values for said at least ten genes upon exposure to the test compound, and wherein said at least ten genes correspond to sequences listed in one of Tables 5-5CC; (c) comparing the gene expression profile to a renal toxicity model, the renal toxicity model comprising information from one or more of Tables 5-5CC, and comprising: (i) the normalized mean expression levels of said at least ten genes in kidney tissue or kidney cells exposed to a known renal toxin, and (ii) the normalized mean expression levels of said at least ten genes in unexposed kidney tissue or kidney cells; and (d) scoring the comparison to determine whether the test compound is a renal toxin.

2. The method of claim 1, wherein the gene expression profile comprises the differential gene expression values for at least 100 genes that correspond to sequences listed in Table 5, and wherein the renal toxicity model comprises the Tox Mean and Nontox Mean gene expression values in Tables 5-5CC.

3. The method of claim 1, wherein said gene expression profile is generated by hybridization of nucleic acids to a microarray, and is normalized for hybridization conditions, label intensity, and reading efficiency prior to comparison.

4. The method of claim 1, wherein the renal toxicity model comprises all the information in any one of Tables 5-5CC.

5. The method of claim 1, wherein the kidney tissue or kidney cells are exposed to the test compound in vivo and the renal toxicity model is generated by exposure of kidney tissue or kidney cells to the known renal toxin in vivo.

6. The method of claim 1, wherein the known renal toxin is associated with at least one of nephritis, kidney necrosis, glomerular or tubular injury, and focal segmental glomerulosclerosis.

7. The method of claim 1, wherein the known renal toxin is one or more of cephaloridine, cisplatin, puromycin aminonucleoside (PAN), bromoethylamine hydrobromide (BEA), gentamicin, ifosfamide, cyclophosphamide, carboplatin, AY-25329, indomethacin, acyclovir, citrinin, mercuric chloride, diflunisal, cidofovir, pamidronate, lithium chloride, hydralazine, coichicine, sulfadiazine, and adriamycin.

8. The method of claim 1, wherein the kidney tissue or kidney cells exposed to the test compound are rat kidney tissue or rat kidney cells, and the renal toxicity model is generated by exposure of rat kidney tissue or rat kidney cells to the known renal toxin.

9. The method of claim 1, wherein the gene expression profile contains the differential gene expression values for at least 20 genes that correspond to sequences listed in Table 5.

10. The method of claim 1, wherein the gene expression profile contains the differential gene expression values for at least 30 genes that correspond to sequences listed in Table 5.

11. The method of claim 1, wherein the known renal toxin is associated with nephrogenic diabetes insipidus.

SEQUENCE LISTING SUBMISSION ON COMPACT DISC

The Sequence Listing submitted concurrently herewith on compact disc under 37 C.F.R. §§1.821(c) and 1.821(e) is herein incorporated by reference in its entirety. Three copies of the Sequence Listing, one on each of three compact discs are provided. Copy 1 and Copy 2 are identical. Copies 1 and 2 are also identical to the CRF. Each electronic copy of the Sequence Listing was created on May 22, 2002 with a file size of 3088 KB. The file names are as follows: Copy 1- gl5089us.txt; Copy 2- gl5089us.txt; CRF-gl5089us.txt.

BACKGROUND OF THE INVENTION

The need for methods of assessing the toxic impact of a compound, pharmaceutical agent or environmental pollutant on a cell or living organism has led to the development of procedures which utilize living organisms as biological monitors. The simplest and most convenient of these systems utilize unicellular microorganisms such as yeast and bacteria, since they are the most easily maintained and manipulated. In addition, unicellular screening systems often use easily detectable changes in phenotype to monitor the effect of test compounds on the cell. Unicellular organisms, however, are inadequate models for estimating the potential effects of many compounds on complex multicellular animals, as they do not have the ability to carry out biotransformations.

The biotransformation of chemical compounds by multicellular organisms is a significant factor in deternining the overall toxicity of agents to which they are exposed. Accordingly, multicellular screening systems may be preferred or required to detect the toxic effects of compounds. The use of multicellular organisms as toxicology screening tools has been significantly hampered, however, by the lack of convenient screening mechanisms or endpoints, such as those available in yeast or bacterial systems. Additionally, previous attempts to produce toxicology prediction systems have failed to provide the necessary modeling data and statistical information to accurately predict toxic responses (e.g., WO 00/12760, WO 00/47761, WO 00/63435, WO 01/32928, and WO 01/38579).

SUMMARY OF THE INVENTION

The present invention is based on the elucidation of the global changes in gene expression in tissues or cells exposed to known toxins, in particular renal toxins, as compared to unexposed tissues or cells as well as the identification of individual genes that are differentially expressed upon toxin exposure.

In various aspects, the invention includes methods of predicting at least one toxic effect of a compound, predicting the progression of a toxic effect of a compound, and predicting the renal toxicity of a compound. The invention also includes methods of identifying agents that modulate the onset or progression of a toxic response. Also provided are methods of predicting the cellular pathways that a compound modulates in a cell. The invention also includes methods of identifying agents that modulate protein activities.

In a further aspect, the invention includes probes comprising sequences that specifically hybridize to genes in Tables 1-5. Also included are solid supports comprising at least two of the previously mentioned probes. The invention also includes a computer system that has a database containing information identifying the expression level in a tissue or cell sample exposed to a renal toxin of a set of genes comprising at least two genes in Tables 1-5.

DETAILED DESCRIPTION

Many biological functions are accomplished by altering the expression of various genes through transcriptional (e.g. through control of initiation, provision of RNA precursors, RNA processing, etc.) and/or translational control. For example, fundamental biological processes such as cell cycle, cell differentiation and cell death, are often characterized by the variations in the expression levels of groups of genes.

Changes in gene expression are also associated with the effects of various chemicals, drugs, toxins, pharmaceutical agents and pollutants on an organism or cell. For example, the lack of sufficient expression of functional tumor suppressor genes and/or the over expression of oncogene/protooncogenes after exposure to an agent could lead to tumorgenesis or hyperplastic growth of cells (Marshall (1991), Cell 64: 313-326; Weinberg (1991), Science 254: 1138-1146). Thus, changes in the expression levels of particular genes (e.g. oncogenes or tumor suppressors) may serve as signposts for the presence and progression of toxicity or other cellular responses to exposure to a particular compound.

Monitoring changes in gene expression may also provide certain advantages during drug screening and development. Often drugs are screened for the ability to interact with a major target without regard to other effects the drugs have on cells. These cellular effects may cause toxicity in the whole animal, which prevents the development and clinical use of the potential drug.

The present inventors have examined tissue from animals (kidney cells) exposed to known renal toxins which induce detrimental kidney effects, to identify global changes in gene expression induced by these compounds (Tables 5-5CC). These global changes in gene expression, which can be detected by the production of expression profiles (an expression level of one or more genes), provide useful toxicity markers that can be used to monitor toxicity and/or toxicity progression by a test compound. Some of these markers may also be used to monitor or detect various disease or physiological states, disease progression, drug efficacy, and drug metabolism.

Identification of Toxicity Markers

To evaluate and identify gene expression changes that are predictive of toxicity, studies using selected compounds with well characterized toxicity have been conducted by the present inventors to catalogue altered gene expression during exposure in vivo and in vitro. In the present study, cephaloridine, cisplatin, puromycin aminonucleoside (PAN), bromoethylamine hydrobromide (BEA), gentamicin, ifosfamide, cyclophosphamide, carboplatin, AY-25329, indomethacin, acyclovir, citrinin, mercuric chloride, diflunisal, cidofovir, pamidronate, lithium, hydralazine, colchicine, sulfadiazine, and adriamycin were selected as known renal toxins.

Cephaloridine is an amphoteric, semi-synthetic, broad-spectrum cephalosporin derived from cephalosporin C. Cephalosporins are β-lactam-containing antibiotics which prevent bacterial growth by inhibiting polymerization of the peptidoglycan bacterial cell wall. The linear glycan chains (composed of N-acetylglucosime and N-acetylmuramic acid) are cross-linked to each other by the coupling of short chains of several amino acids, the coupling resulting from the action of a transpeptidase. It is believed that cephalosporins act by blocking the activity of the transpeptidase ( Goodman & Gilman's The Pharmalogical Basis of Therapeutics 9 ^th ed ., J. G. Hardman et al. Eds., McGraw Hill, New York, 1996, pp. 1074-1075, 1089-1095).

Cephaloridine is administered intramuscularly and is used to treat infections of the respiratory tract, gastrointestinal tract and urinary tract, as well as infections of soft tissue, bones and joints. Noted adverse effects include hypersensitivity reactions (such as anaphylactic shock, urticaria and bronchospasm), gastrointestinal disturbances, candidiasis, and cardiovascular and blood toxicity, in particular, toxicity to the hematopoietic system (cells responsible for the formation of red and white blood cells and platelets).

Although cephaloridine may be nephrotoxic at high dosages, it is not as harmful to the kidneys as are the aminoglycosides and polymixins. High dosages of cephaloridine may cause acute renal tubular necrosis ( Cecil Textbook of Medicine , 20 ^th ed., part XII , p. 586, J. C. Bennett and F. Plum Eds., W. B. Saunders Co., Philadelphia, 1996) or drug-induced interstitial nephritis, which is accompanied by elevated IgE levels, fever, arthralgia and maculopapular rash. Renal biopsopy demonstrates edema and interstitial inflammatory lesions, mainly with lymphocytes, monocytes, eosinophils and plasma cells. Vasculitis of small vessels may develop, leading to necrotising glomerulonephritis (G. Koren, “The nephrotoxic potential of drugs and chemicals. Pharmacological basis and clinical relevance.,” Med Toxicol Adverse Drug Exp 4(1):59-72, 1989).

Cephaloridine has also been shown to reduce mitochondrial respiration and uptake of anionic succinate and carrier-mediated anionic substrate transport (Tune et al. (1990), J Pharmacol Exp Ther 252: 65-69). In a study of oxidative stress and damage to kidney tissue, cephaloridine depleted reduced glutathione (GSH) and produced oxidized glutathione (GSSG) in the renal cortex. This drug also inhibited glutathione reductase and produced malondialdehyde and conjugated dienes (Tune et al. (1989), Biochem Pharmacol 38: 795-802). Because cephaloridine is actively transported into the proximal renal tubule, but slowly transported across the lumenal membrane into the tubular fluid, high concentrations can accumulate and cause necrosis. Necrosis can be prevented by administering inhibitors of organic anion transport, although such treatment may be counterproductive, as cephaloridine is passed in and out of the kidney by the renal organic anion transport system (Tune et al. (1980), J Pharmacol Exp Ther 215: 186-190).

Cisplatin (Pt(NH ₃ ) ₂ (Cl) ₂ ), a broad-spectrum anti-tumor agent, is commonly used to treat tumors of the testicles, ovaries, bladder, skin, head and neck, and lungs (PDR 47 ^th ed., pp. 754-757, Medical Economics Co., Inc., Montvale, N.J., 1993 ; Goodman & Gilman's The Pharmalogical Basis of Therapeutics 9 ^th ed ., pp. 1269-1271, J. G. Hardman et al. Eds., McGraw Hill, New York, 1996). Cisplatin diffuses into cells and functions mainly by alkylating the N ⁷ of guanine, a highly reactive site, causing interstrand and intrastrand crosslinks in the DNA that are lethal to cells. The drug is not sensitive to the cell cycle, although its effects are most pronounced in S phase.

Because the drug is cleared from the body mainly by the kidneys, the most frequent adverse effect of cisplatin usage is nephrotoxicity, the severity of which increases with increasing dosage and treatment terms. Other adverse effects include renal tubule damage, myelosuppression (reduced numbers of circulating platelets, leukocytes and erythrocytes), nausea and vomiting, ototoxicity, serum electrolyte disturbances (decreased concentrations of magnesium, calcium, sodium, potassium and phosphate, probably resulting from renal tubule damage), increased serum concentrations of urea and creatinine, and peripheral neuropathies.

In one study on rats (Nonclercq et al. (1989), Exp Mol Pathol 51: 123-140) administration of cisplatin or carboplatin induced renal injury, carboplatin causing less damage than cisplatin. The most prominent injury was to the straight portion of proximal renal tubule.

In another rat study (Goldstein et al. (1981), Toxicol Appl Pharmacol 60: 163-175) animals injected with cisplatin displayed decreased food intake as drug dosage increased. On day 2, the high-dose groups (10-15 mg/kg) exhibited a six or seven-fold elevation in BUN. On day 4, BUN elevation was noted in the 5 mg/kg group. An increase in urine volume was observed beginning on days 3-4, along with decreased urine osmolality in the low-dose groups (2.5 or 5 mg/kg). Another experiment on rats (Agarwal et al. (1995), Kidney Int 48: 1298-1307) showed that cisplatin treatment produced elevations in serum creatinine levels, which began on day 3 and progressed for the duration of the study.

PAN (C ₂₂ H ₂₉ N ₇ O ₅ ), an antibiotic produced by Streptomyces alboniger , inhibits protein synthesis and is commonly used experimentally on rats to mimic human minimal change disease. One study showed that PAN-injected rats demonstrated an increase in levels of serum non-esterified fatty acids, while the serum albumin concentration was negatively affected (Sasaki et al. (1999), Adv Exp Med Biol 467: 341-346).

In another rat study, an adenosine deaminase inhibitor prevented PAN nephrotoxicity, indicating that PAN toxicity is linked to adenosine metabolism (Nosaka et al. (1997), Free Radic Biol Med 22: 597-605). Another group showed that PAN, when administered to rats, led to proteinuria, a condition associated with abnormal amounts of protein in the urine, and renal damage, e.g. blebbing of glomerular epithelial cells, focal separation of cells from the glomerular basement membrane, and fusion of podocytes (Olson et al. (1981), Lab Invest 44: 271-279). In another study on rats, administration of PAN induced glomerular epithelial cell apoptosis in a dose- and time-dependent manner (Sanwal et al. (2001), Exp Mol Pathol 70: 54-64).

One study with PAN-injected rats (Koukouritaki et al. (1998), J Investig Med 46: 284-289) examined the changes in the expression of the proteins paxillin, focal adhesion kinase, and Rho, all of which regulate cell adhesion to the extracellular matrix. Paxillin levels increased steadily, peaked at day 9 after PAN injection, and then remained elevated even after proteinuria resolved. There was no observed change in expression of either focal adhesion kinase or Rho.

BEA, (C ₂ H ₆ BrN.HBr), is commonly used experimentally on rats to induce papillary necrosis and renal cortex damage, which is similar to human analgesic nephropathy. BEA-induced papillary necrosis in rats eventually leads to the onset of focal glomerular sclerosis and nephrotic proteinuria (Garber et al. (1999), Am J Kidney Dis 33: 1033-1039). Even at low doses (50 mg/kg), BEA can induce an apex limited renal papillary necrosis (Bach et al. (1983), Toxicol Appl Pharmacol 69: 333-344). In male Wistar rats, BEA administered at 100 mg/kg was shown to cause renal papillary necrosis within 24 hours (Bach et al. (1991), Food Chem Toxicol 29: 211-219). Additionally, Bach et al. showed that there was an increase in urinary triglycerides, and lipid deposits were seen by Oil Red O lipid staining in the cells of the collecting ducts and hyperplastic urothelia adjacent to the necrosed region.

It has also been shown that succinate and citrate concentrations are significantly lower in the urine of BEA-treated rats (Holmes et al. (1995), Arch Toxicol 70: 89-95). Moreover, BEA treatment induced glutaric and adipic aciduria, which is symptomatic of an enzyme deficiency in the acyl CoA dehydrogenases. The same study examined urinary taurine levels in desert mice, and in BEA-treated desert mice there was an increase in the urinary taurine level which is indicative of liver toxicity.

Another study on BEA-treated rats showed that there was an increase in the concentrations of creatine in the renal papilla and glutaric acid in the liver, renal cortex, and renal medulla as soon as 6 hours post-treatment (Garrod et al. (2001), Magn Reson Med 45: 781-790).

Discovered and purified in the early 1960's, gentamicin is a broad-spectrum aminoglycoside antibiotic that is cidal to aerobic gram-negative bacteria and commonly used to treat infections, e.g., those of the urinary tract, lungs and meninges. As is typical for an aminoglycoside, the compound is made of two amino sugar rings linked to a central aminocyclitol ring by glycosidic bonds. Aminoglycosides are absorbed poorly with oral administration, but are excreted rapidly by the kidneys. As a result, kidney toxicity is the main adverse effect, although ototoxicity and neuromuscular blockade can also occur. Gentamicin acts by interfering with bacterial protein synthesis. This compound is more potent than most other antibacterial inhibitors of protein synthesis, which are merely bacteriostatic, and its effects on the body are, likewise, more severe ( Goodman & Gilman's The Pharmalogical Basis of Therapeutics 9 ^th ed ., pp. 1103-1115, J. G. Hardman et al. Eds., McGraw Hill, New York, 1996).

Aminoglycosides work rapidly, and the rate of bacterial killing is concentration-dependent. Residual bactericidal activity remains after serum concentration has fallen below the minimum inhibitory concentration (MIC), with a duration that is also dosage/concentration-dependent. The residual activity allows for once-a-day administration in some patients. These drugs diffuse into bacterial cells through porin channels in the outer membrane and are then transported across the cytoplasmic membrane via a m