Antimicrobial efficacy of n-[3- chloro-(substituted aryl)-4-oxoazetidin- 1-yl] pyridine-4- carboxamides against resistant bacterial strains obtained from clinical isolates
Keywords:2-Azetidinone, Antimicrobial, Î²-lactamase inhibitory, Multi-drug resistant strains
Background: The treatment of infectious diseases is still an important and challenging problem due to emerging infectious diseases and increasing number of multi-drug resistant microbial pathogens which cause a variety of illnesses ranging from hospital-acquired pneumonia, bloodstream infections, urinary tract infections from catheters, abdominal infections and even meningitis.
Methods: The main objective of the present study was to evaluate the antimicrobial efficacy and Î²-lactamase inhibitory activity of the synthesized 2-azetidinones against resistant bacterial strains obtained from clinical isolates.
Results: The tested 2-azetidinones exhibited antimicrobial efficacy comparable to the standard drugs Ampicillin and Griseofelvin. Among the tested compounds, N-[3-chloro-2-(2,5-dimethoxyphenyl)-4-oxoazetidin-1-yl]pyridine-4-carboxamide(5o) exhibited the highest activity with MIC of 6.25 Âµg/mL (Gram +ve and Gram â€“ve bacteria),1.56 Âµg/mL (A. niger) and 3.12 Âµg/mL(A. terrus and P. chrysogenum) respectively. Also all the screened compounds (5d, 5f, 5h,5j,5o) exhibited more pronounced activity (MIC: 125 Âµg/mL) against resistant K. pneumonia obtained from clinical isolates compared to standard antibiotic Amoxycillin. The compounds when tested as admixtures with the standard antibiotic amoxicillin (1:2) exhibited similar antibacterial spectra in comparison to the most widely employed clinical combination Augmentin. The 2-azetidinones
can prove to be a cheaper alternative with similar potential Î²-lactamase inhibitory activity thereby proving their utility and benefit towards the development of anti-infectives for the treatment of infections caused by drug resistant microorganisms.
Cohn, ML. Epidemiology of Drug Resistance: Implications for a Post-Antimicrobial Era. Science. 1992; 257(5073):1050-1055.
Tenover, FC. Mechanisms of Antimicrobial Resistance in Bacteria. The American Journal of Medicine. 2006; 119 (6A): S3â€“S10.
National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004; 32:470-485.
Chambers, HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001; 7:178 â€“182.
Jones, RN, Kirby, JT, Beach, ML, Biedenbach, DJ and Pfaller, MA. Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997â€“2000). Diagn Microbiol Infect Dis. 2002; 43:239-243.
Kang CI, Kim SH and Park WB. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. AntimicrobAgents Chemother. 2005; 49:760-766.
Ibrahim, EH, Sherman, G, Ward, S, Fraser, VJ and Kollef, MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000; 118:146-155.
Canton, R, Coque, TM and Baquero, F. Multi-resistant gram-negative bacilli: from epidemics to endemics. Curr. Opin. Infect. Dis. 2003; 16(4): 315-325.
Stevens, DL. Community-acquired Staphylococcus aureus infections: Increasing virulence and emerging methicillin resistance in the new millennium. Curr. Opin. Infect. Dis. 2003; 16(3):189-191.
Levy, SB and Marshall, B. Antibacterial resistance worldwide: causes, challenges and responses. Nat. Med. 2004; 10(12 Suppl):S122-129.
Perfeito, L, Fernandes, L, Catarina, M and Gordo, I. Adaptive Mutations in Bacteria:High Rate and Small Effects. Science. 2007; 317(5839): 813-815.
Salyers, AA, Gupta, A and Wang, Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol. 2004; 12(9): 412-416.
Paterson, DL and Bonomo, RA. Extended-spectrum beta-lactamases. A clinical update. Clin. Microbiol. Rev. 2005; 18 (4): 657-686.
Yigit, H, Queenan, AM, Anderson, GJ, Domenech-Sanchez, A, Steward, CD, Biddle, JW, Alberti, CDS, Bush, K and Tenover, FC. Novel carbapenem-hydrolyzing beta-lactamase,
KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 2001; 45(4):1151-1161.
Gupta, V, Datta, P, Agnihotri, N and Chander, J. Comparative in vitro activities of seven new Î²-lactams, alone and in combination with Î²-lactamase inhibitors, against clinical isolated resistant to third generation cephalosporins. The Brazilian journal of infectious diseases. 2006; 10(1): 22-25.
Sykes, RB, Cimarusti, CM, Bonner, DP, Bush, K, Floyd, DM, Koster, WH, Georgopapadakou, NH and Liu, WC. Monocyclic Î²-lactam antibiotics produced by bacteria. Nature. 1981; 291(5815): 489-491.
Singh, GS and Luntha P. Synthesis and antimicrobial activity of new 1-alkyl/cyclohexyl-3,3-diaryl-1â€²-methylspiro[azetidine-2,3â€²-indoline]-2â€²,4-diones.Eur. J. Med. Chem.2009; 44(5): 2265-2269.
Halve, AK, Bhadauria, D and Dubey, R. N/C-4 substituted azetidin-2-ones: Synthesis and preliminary evaluation as new class of antimicrobial agents. Bioorg. Med. Chem. Lett. 2007; 17(2): 341-345.
Chavan, AA and Pai, NR. Synthesis and Biological Activity of N-Substituted-3-chloro-2-azetidinones . Molecules 2007; 12(11): 2467-2477.
Broccolo, F, Cainelli, G, Caltabiano, G, Cocuzza, CEA, Fortuna, CG, Galletti, P, Giacomini, D, Musumarra, G, Musumeci, R and Quintavalla, A. Design, Synthesis, and Biological Evaluation of 4-Alkyliden-beta Lactams: New Products with Promising Antibiotic Activity Against Resistant Bacteria. J. Med. Chem. 2006; 49(9):2804-2811.
Desai, KG and Desai, KR. Green route for the heterocyclization of 2-mercaptobenzimidazole into Î²-lactum segment derivatives containing â€“CONH- bridge with benzimidazole: Screening in vitro antimicrobial activity with various microorganisms. Bioorg. Med. Chem. 2006; 14(24): 8271-8279.
Singh, GS, Mbukwa, E and Pheko, T. Synthesis and antimicrobial activity of new 2-azetidinones from N-(salicylidene)amines and 2-diazo-1,2-diarylethanones. ARKIVOC 2007; (ix): 80-90.
Bush, K, Jacoby, GA and Medeiros, A.A. A functional classification scheme for ÃŸ-lactamases and its correlation to molecular structure. Antimicrob. Agents Chemother. 1995; 39:1211-1233.
Sirot, D, Chanal, C, Henquell, C, Labia, R and Sirot, J . Molecular characterization of nine different types of mutants among 107 inhibitor-resistant TEM beta-lactamases from clinical isolates of Escherichia coli. Antimicrob. Chemother. 1995; 39(2): 427-430.
Singh, GS and Mmolotsi, BJ. Synthesis of 2-azetidinones from 2-diazo-1, 2-diarylethanones and N-(2-thienylidene) imines as possible antimicrobial agents.
Il Farmaco.2005; 60(9): 727-730.
Thomas, AB, Nanda, RK, Kothapalli, LP and Hamane, SC. Synthesis and biological evaluation of Schiffâ€™s bases and 2-azetidinones of isonicotiniyl hydrazone as potential antidepressant and nootropic agents. Arabian Journal Chemistry(In Press).
Thomas, AB, Tupe, PN, Badhe, RV, Nanda, RK, Kothapalli, LP, Paradkar, OD, Sharma, PA and Deshpande, AD. Green route synthesis of Schiffâ€™s bases of Isonicotinic acid hydrazide. Green Chem. Lett. Rev. 2009; 2(1): 23-29.
Thomas, AB, Paradkar, OD, Nanda, RK, Tupe, PN, Sharma, PA, Badhe, RB, Kothapalli, LP, Banerjee, AR, Hamane, SC and Deshpande AD. Eco friendly method for the synthesis of Azetidinones of Isonicotinic acid hydrazide. Green Chem. Lett. Rev. 2010; 3(4): 293-300.
Thomas, AB, Nanda, RK, Kothapalli, LP and Deshpande, AD. Synthesis and antimicrobial activity of N-[2- (aryl/substituted aryl)-4-oxo-1, 3-thiazolidin-3-yl] pyridine-4-carboxamide. Journal of Korean Chemical Society. 2011; 55(6):960-968.
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