Molecular Modifications of Antimicrobial Agents to Overcome Drug Resistance

: No doubt antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of infections. Due to widespread emergence of resistance, even the new families of antimicrobial agents have a short life expectancy. Drugs acting on single target often lead to drug resistance and are associated with various side effects. To overcome this problem either multidrug therapy or single drug acting on multiple targets may be used. The later are called ‘hybrid molecules’ which are formed by clubbing two biologically active pharmacophores together with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy to combat drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions improving the solubility and binding affinity to biomolecular targets. In this review we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential antibacterial agents aiming to provide a useful platform for the exploration of new leads with broader spectrum, more effectiveness, less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

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Inducible Macrolide Resistance inCorynebacterium jeikeium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.7.1982-1989.2001 ◽

2001 ◽

Vol 45 (7) ◽

pp. 1982-1989 ◽

Cited By ~ 37

Author(s):

Adriana E. Rosato ◽

Bonnie S. Lee ◽

Kevin A. Nash

Keyword(s):

Drug Resistance ◽

Resistance Genes ◽

Broad Spectrum ◽

Antimicrobial Agents ◽

Opportunistic Pathogen ◽

Macrolide Resistance ◽

The Other ◽

Broad Spectrum Resistance ◽

Neutropenic Patients ◽

Group 3

ABSTRACT Corynebacterium jeikeium is an opportunistic pathogen primarily of immunocompromised (neutropenic) patients. Broad-spectrum resistance to antimicrobial agents is a common feature of C. jeikeium clinical isolates. We studied the profiles of susceptibility of 20 clinical strains of C. jeikeium to a range of antimicrobial agents. The strains were separated into two groups depending on the susceptibility to erythromycin (ERY), with one group (17 strains) representing resistant organisms (MIC > 128 μg/ml) and the second group (3 strains) representing susceptible organisms (MIC ≤ 0.25 μg/ml). The ERY resistance crossed to other members of the macrolide-lincosamide-streptogramin B (MLSb) group. Furthermore, this resistance was inducible with MLSb agents but not non-MLSb agents. Expression of ERY resistance was linked to the presence of an allele of the class X erm genes,erm(X)cj, with >93% identity to other ermgenes of this class. Our evidence indicates that erm(X)cj is integrated within the chromosome, which contrasts with previous reports for the plasmid-associated erm(X) genes found inC. diphtheriae and C. xerosis. In 40% ofC. jeikeium strains, erm(X)cj is present within the transposon, Tn5432. However, in the remaining strains, the components of Tn5432 (i.e., the erm and transposase genes) have separated within the chromosome. The rearrangement of Tn5432 leads to the possibility that the other drug resistance genes have become included in a new composite transposon bound by the IS1249 elements.

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Drug resistance and plasmid profile of shigellae in Taiwan

Epidemiology and Infection ◽

10.1017/s0950268800049530 ◽

1992 ◽

Vol 108 (1) ◽

pp. 87-97 ◽

Cited By ~ 7

Author(s):

S.-R. Lin ◽

S.-F. Chang

Keyword(s):

Drug Resistance ◽

Antimicrobial Agents ◽

Plasmid Profile ◽

Resistance Pattern ◽

Multiple Resistance ◽

College Hospital ◽

Medical College ◽

Transmissible Plasmid ◽

Resistance Patterns ◽

Species Specific

SUMMARYOne hundred and twenty-eight shigella strains isolated from newborn and infant human faecal specimens at Kaohsiung Medical College Hospital in Taiwan were serogrouped, serotyped and examined for drug-resistance patterns and for the presence of plasmids. Forty-seven pre cent of the isolates were found to belong to theShigella sonneiserogroup, 41%to theS.flexnerigroup,9%to theS.boydiigroup and 3%to theS.dysenteriaegroup.The serotype with the greatest number of strains wasS.sonneiI. (29 %) followed byS. flexneri1 (27%). Each strain was tested for resistance to 11 antimicrobial agents. Eighty-eight per cent of the strains were resistant to tetracycline, 87% to chloramphenicol, 84% to streptomycin, 52% to ampicillin, 25% to nalidixic acid, 29% to kanamycin, 11 % to cephalothin, 11% to neomycin, 10% to cotrimoxazole, 1% to amikacin and none to gentamicin. The most prevalent resistance pattern was ApCmSmTc (28%). Clinical isolates demonstrating multiple resistance were found to harbour a large transmissible plasmid of 45–75 MDa while isolates without multiple resistance did not. Two large virulence plasmids of 123 and 110 MDa were found in 12 strains ofS. flexneriand 4 strains ofS. sonneiphase I. Small plasmids of 4·5, 4·2, 3·5, 2·8, 2·5. 2·0 and 1·5 MDa were also present in all strains. These small plasmids were species specific and can be used as marker plasmids to identify species.

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Clinical and drug resistance characteristics of Providencia stuartii infections in 76 patients

Journal of International Medical Research ◽

10.1177/0300060520962296 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006052096229

Author(s):

Jiachang Liu ◽

Ruikai Wang ◽

Ming Fang

Keyword(s):

Drug Resistance ◽

Antimicrobial Agents ◽

Multiple Drug Resistance ◽

Drug Susceptibility ◽

Fourth Generation ◽

Multiple Drug ◽

Beta Lactam ◽

Hospital Department ◽

Extended Spectrum Beta Lactamase ◽

Providencia Stuartii

Objectives To investigate the clinical and drug resistance characteristics of Providencia stuartii infections in the Huainan region of Anhui and provide a reference for the clinical selection of antimicrobial agents. Methods This single-center retrospective analysis included 76 patients with P. stuartii infection in Huainan during the period from October 2018 to March 2020. The hospital department in which the patients were treated and the drug susceptibility characteristics of the P. stuartii isolates were recorded. Results Among the 76 patients, the lung was the most common site of infection, and intensive care unit was the main hospital department. Extended spectrum beta-lactamase screening revealed expression by all 76 isolates of P. stuartii. Of the 76 isolates, 92.1% exhibited multiple drug resistance or extensive drug resistance. P. stuartii isolates were sensitive to cefepime and imipenem, but not to other beta-lactam antibiotics. Twenty isolates were resistant to all 21 types of antibiotics. Of the 20 patients infected with extensively drug-resistant isolates, nine (45%) died. Conclusions Drug resistance is increasing in P. stuartii. The antimicrobial agent imipenem may be effective for treatment of P. stuartii infections. Fluoroquinolones, aminoglycosides, and fourth-generation cephalosporins are suitable options for antibiotic therapy.

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Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance

mBio ◽

10.1128/mbio.00996-20 ◽

2020 ◽

Vol 11 (3) ◽

Cited By ~ 5

Author(s):

Meinan Lyu ◽

Mitchell A. Moseng ◽

Jennifer L. Reimche ◽

Concerta L. Holley ◽

Vijaya Dhulipala ◽

...

Keyword(s):

Electron Microscopy ◽

Drug Resistance ◽

Neisseria Gonorrhoeae ◽

Antimicrobial Agents ◽

Efflux Pump ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Transmitted Infection ◽

Content Type ◽

Cryo Electron Microscopy

ABSTRACT Neisseria gonorrhoeae is an obligate human pathogen and causative agent of the sexually transmitted infection (STI) gonorrhea. The most predominant and clinically important multidrug efflux system in N. gonorrhoeae is the multiple transferrable resistance (Mtr) pump, which mediates resistance to a number of different classes of structurally diverse antimicrobial agents, including clinically used antibiotics (e.g., β-lactams and macrolides), dyes, detergents and host-derived antimicrobials (e.g., cationic antimicrobial peptides and bile salts). Recently, it has been found that gonococci bearing mosaic-like sequences within the mtrD gene can result in amino acid changes that increase the MtrD multidrug efflux pump activity, probably by influencing antimicrobial recognition and/or extrusion to elevate the level of antibiotic resistance. Here, we report drug-bound solution structures of the MtrD multidrug efflux pump carrying a mosaic-like sequence using single-particle cryo-electron microscopy, with the antibiotics bound deeply inside the periplasmic domain of the pump. Through this structural approach coupled with genetic studies, we identify critical amino acids that are important for drug resistance and propose a mechanism for proton translocation. IMPORTANCE Neisseria gonorrhoeae has become a highly antimicrobial-resistant Gram-negative pathogen. Multidrug efflux is a major mechanism that N. gonorrhoeae uses to counteract the action of multiple classes of antibiotics. It appears that gonococci bearing mosaic-like sequences within the gene mtrD, encoding the most predominant and clinically important transporter of any gonococcal multidrug efflux pump, significantly elevate drug resistance and enhance transport function. Here, we report cryo-electron microscopy (EM) structures of N. gonorrhoeae MtrD carrying a mosaic-like sequence that allow us to understand the mechanism of drug recognition. Our work will ultimately inform structure-guided drug design for inhibiting these critical multidrug efflux pumps.

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Likelihood of Inadequate Treatment A Novel Approach to Evaluating Drug-Resistance Patterns

Infection Control and Hospital Epidemiology ◽

10.1086/598245 ◽

2009 ◽

Vol 30 (7) ◽

pp. 672-677 ◽

Cited By ~ 7

Author(s):

Heinz Burgmann ◽

Brigitte Stoiser ◽

Gottfried Heinz ◽

Peter Schenk ◽

Petra Apfalter ◽

...

Keyword(s):

Drug Resistance ◽

Antimicrobial Agents ◽

Rank Order ◽

Tertiary Care ◽

Daily Practice ◽

University Teaching ◽

Ventilator Associated Pneumonia ◽

Adequate Therapy ◽

Resistance Rates ◽

Microbiological Data

Objective.To provide a novel way to predict the likelihood that antibiotic therapy will result in prompt, adequate therapy on the basis of local microbiological data.Design and Setting.Prospective study conducted at 3 medical intensive care units at the Viennese General Hospital, a tertiary care medical university teaching hospital in Vienna, Austria.Patients.One hundred one patients who received mechanical ventilation and who met the criteria for having ventilator-associated pneumonia.Design.Fiberoptic bronchoscopic examination was performed, and bronchoalveolar samples were collected. Samples were analyzed immediately by a single technician. Minimum inhibitory concentrations were determined for imipenem, cephalosporins (cefepime and cefpirome), ciprofloxacin, and piperacillin-tazobactam, and drug resistance rates were calculated. These drug resistance rates were translated into the likelihood of inadequate therapy (LIT; the frequency of inadequately treated patients per antibiotic and drug-resistant strain), cumulative LIT (the cumulative frequency of inadequately treated patients), and syndrome-specific LIT.Results.Amongthe 101 bronchoalveolar samples, culture yielded significant (at least 1 × 104 colony-forming units per raL) polymicrobial findings for 34 and significant monomicrobial findings for 31; 36 culture results were negative. Of the isolates from patients with ventilator-associated pneumonia who had monomicrobial culture findings, 33% were gram-positive bacteria and 20% were gram-negative bacteria. LIT suggested that 1 of 2 patients was treated inadequately for Pseudomonas aeruginosa infection. The LIT for patients with ventilator-associated pneumonia revealed that the rank order of antibiotics for appropriate therapy was (1) imipenem, (2) cephalosporins, (3) ciprofloxacin, and (4) piperacillin-tazobactam. These calculations were based solely on microbiological data.Conclusions.The novel ratio LIT may help clinicians use microbiological data on drug resistance to predict which antimicrobial agents will provide adequate therapy. In daily practice, this new approach may be helpful for choosing adequate antimicrobial therapy.

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Detection of Pan drug resistance OXA-48 producing Providencia in an ICU patient for the first time in Nepal

Antimicrobial Resistance and Infection Control ◽

10.1186/s13756-019-0608-1 ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 3

Author(s):

Ranjit Sah ◽

Shusila Khadka ◽

Gentle Sunder Shrestha ◽

Subhash Acharya ◽

Diptesh Aryal ◽

...

Keyword(s):

Drug Resistance ◽

Pathogenic Bacteria ◽

Antimicrobial Agents ◽

Vital Signs ◽

Carbapenem Resistance ◽

Diffusion Method ◽

Resistance Pattern ◽

Common Mechanism ◽

Disk Diffusion Method ◽

Drug Resistance Pattern

Abstracts Background Resistance to antimicrobial agents of pathogenic bacteria has become a major problem in routine medical practices. Carbapenem resistance has long been increasing. The production of carbapenem- hydrolysing β-lactamases (carbapenamases), which include NDM, KPC, OXA-48, IMP-1 and VIM is the most common mechanism. Case presentation A 56 years old male presented with fever and mental changes with progressively decreasing sensorium for the last 3 days. He was admitted to Intensive care unit (ICU) with a diagnosis of meningoencephalitis. On day seven, he developed ventilator associated pneumonia due Klebsiella pnemoniae and Acinetobacter baumannii. He was on meropenem, but the isolates were susceptible to colistin, tigecyclin and amikacin solely. Hence, amikacin was started with addition of intravenous and nebulized colistin. Subsequently, vital signs improved with resolution of fever. However, on day 18, he developed fever once again with a drop in blood pressure. Inotropic support was maintained, and echinocandins and tigecycline were added to the regimen. Repeat blood and urine culture grew Providencia species, which were resistant to most of the drugs on phenotypic Kirby-Bauer disk diffusion method and are intrinsically resistant to colistin and tigecycline. Phenotypic detection of ESBL (combined disk method), MBL, KPCs, AmpC and co-producer were tested according to updated CLSI guideline and all were negative. But the Modified Hodges test was found to be positive. Consequenty, OXA-48 drug resistance pattern was brought into action by blank disc method according to A Tsakris et al., which revealed indentation of growth toward both EDTA and EDTA/PBA disk indicating production of OXA-48 carbapenamase. To confirm the resistance pattern we processed the isolated colonies for Xpert Carba-R (Cepheid) assay, which detected blaOXA-48 gene and confirmed the OXA-48 drug resistance pattern. Hence, the infecting organism was not susceptible to any of the antibiotics. The patient was kept under isolation and on 31th day of admission, he died of septic shock. Conclusions Carbapenamase production along with intrinsic colistin resistance in infecting bacterial pathogens can cause fatal outcomes in the resource limited countries like Nepal where new antibiotic combinations ceftazidime+ Avibactam, or aztreonam +avibactam are not available. Drug resistance patterns including OXA 48 producer should be characterized in all cases by standard phenotypic methods or by Xpert Carba-R assay and larger studies are required to know the exact burden of OXA 48 producer in Nepal.

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Inoculum size effects in blaIMP-6 and plasmid-mediated quinolone resistance gene-positive Enterobacteriaceae in Japan

10.1101/534958 ◽

2019 ◽

Author(s):

Yoshihiko Ogawa ◽

Ryuichi Nakano ◽

Kei Kasahara ◽

Tomoki Mizuno ◽

Nobuyasu Hirai ◽

...

Keyword(s):

Escherichia Coli ◽

Drug Resistance ◽

Klebsiella Pneumoniae ◽

Size Effect ◽

Resistance Gene ◽

Size Effects ◽

Antimicrobial Agents ◽

Inoculum Size ◽

Experimental Strains

AbstractThe aim of this study was to examine the resistance genes in clinical isolates which produced IMP-6 type metallo-β-lactamase lactamase (MBL) and had mildly reduced susceptibilities to levofloxacin and/or amikacin. The inoculum size effect was also assessed. A total of 14 Enterobacteriaceae isolates (2 Escherichia coli and 12 Klebsiella pneumoniae) which produced IMP-6 MBL, and had mild increases in their MICs for levofloxacin and amikacin were examined. Thirteen out of 14 isolates harbored CTX-M-2, with the remaining isolate co-harboring CTX-M-2 and CTX-M-1 as ESBLs. All isolates carried one or more PMQRs; aac(6′)-Ib-cr was the most prevalent (92.8%), followed by oqxA (64.3%), qnrS (42.9%), oqxAB (21.4%), and qnrB (14.3%). The inoculum size effects were significant in all strains for meropenem, 13 for imipenem, 7 for levofloxacin, and 3 for amikacin. Conjugation was successfully performed with 8 isolates and 11 strains were obtained. Eleven of the experimental strains (100%), and 8 strains (72.7%) showed inoculum size effects for meropenem and imipenem, respectively. No inoculum size effect was seen for levofloxacin. Four strains harbored qnr genes and 2 strains harbored qnr genes and QRDR mutations concurrently. blaIMP-6 positive Enterobacteriaceae with mildly reduced susceptibilities to levofloxacin and/or amikacin also harbored at least one plasmid-mediated drug resistance gene. These represent an unrecognized threat, capable of compromising the in vitro activity of many classes of antimicrobial agents. We conclude that IMP-6 MBL plays an important role in decreasing the MIC for carbapenems, whereas qnr does not for levofloxacin.

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To determine antimicrobial susceptibility and biofilm production among coagulase negative staphylococci at a tertiary care hospital

Indian Journal of Microbiology Research ◽

10.18231/j.ijmr.2021.047 ◽

2021 ◽

Vol 8 (3) ◽

pp. 230-234

Author(s):

Naga Sri Latha Bathala ◽

M Sasidhar ◽

S Kusuma Bai

Keyword(s):

Drug Resistance ◽

Antimicrobial Susceptibility ◽

Biofilm Formation ◽

Antimicrobial Agents ◽

Tertiary Care ◽

Multi Drug Resistance ◽

Clinical Samples ◽

Care Hospital ◽

Coagulase Negative Staphylococci ◽

Cross Sectional

CoNS are gaining importance due to increase in resistance rates to betalactam antibiotics and multi drug resistance. Although specific virulence factors are not as clearly established, it seems clear that factors such as bacterial polysaccharide components, and ability to form biofilm are involved in attachment and/or persistence of bacteria on foreign materials. Biofilms usually result in persistent infections that cannot be easily resolved with standard antibiotic treatments; therefore, the biofilm formation ability and the resistance to antimicrobial therapy can be intimately related. A prospective cross-sectional study was done on purely isolated CoNS from various clinical samples from both out patients and inpatients. All the test strains were subjected to antimicrobial susceptibility testing. The ability to produce biofilm was detected by tube adherence method. Among 193 CoNS isolates 156 were from inpatients and 37 were from out patients. Methicillin resistant was seen in 80.31%. Of the total, 40.41% showed moderate biofilm formation by tube adherence method. 23.32% of isolates did not form biofilm. All the isolates from blood samples showed moderate (20/26) and strong (6/26) biofilm formation. Among non biofilm producers 66.67% were MS CoNS isolates and 33.33% were MRCoNS. 94.59% of biofilm producers were MRCoNS and 5.41% were MSCoNS. Production of biofilm was relatively more (1.16) among CoNS isolates of IPD than OPD. As Coagulase negative Staphylocooci are exhibiting multi drug resistance and are able to form biofilm, these organisms causing a major challenge for the physicians. Hence, such problems can be prevented by detection of biofilm producers and appropriate antibiotic doses modification. The issue of antibiotic resistance among CoNS needs to be addressed through a more rational use of existing antibiotics as well as the development of new antimicrobial agents.

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Antimicrobial resistance of non-clinical Escherichia coli strains from chicken in Nsukka, South-east Nigeria.

Nigerian Journal of Animal Production ◽

10.51791/njap.v30i1.1840 ◽

2021 ◽

Vol 30 (1) ◽

pp. 101-106

Author(s):

K. F. Chah ◽

S. C. Okafor ◽

S. I. Oboegbulem

Keyword(s):

Escherichia Coli ◽

Drug Resistance ◽

Antimicrobial Resistance ◽

Antimicrobial Agents ◽

Diffusion Method ◽

Disc Diffusion ◽

Disc Diffusion Method ◽

E Coli ◽

Sensitivity Tests ◽

Resistance Patterns

This study was carried out to determine resistance profiles of Escherichia coli strains isolated from clinically healthy chickens in Nsukka, southeast Nigeria. A total of 324 E. coli strains isolated from cloaca swabs from 390 chickens were tested against 16 antimicrobial agents using the disc diffusion method. The antibiotics used in the study were: ampicillin (25µg), amoxycillin-clavulanic acid (30µg), gentamicin (10µg), Streptomycin (30µg). cefuroxime (20µg), cephalexin (10µg), nalidixic acid (30µg), ciprofloxacin (5µg), norfloxacin (10µg), ofloxacin (5µg), pefloxacin (5µg), tetracycline (30µg), chloramphenicol (10µg), cotrimoxazole (50µg), colistin (25µg) and nitrofurantoin (100µg).The strains demonstrated high rates of resistance (34.6% 66.1%) to ampicillin, tetracycline, nitrofurantoin, cefuroxime and cotrimoxazole. None of the isolates was resistant to colistin, ofloxacin and pefloxacin. For each antimicrobial agent (except cephalexin), strains from the intensively reared chickens (layers and broilers) displayed higher resistance frequencies than those from the local birds. A total of 49 resistant patterns were recorded for the 228 strains resistant to at least one antimicrobial drug, with AmTeCoS and AmTeCfN being the predominant patterns. Because of the great variation in the drug resistance patterns of the Escherichia coli strains, use of antimicrobial agents in the management of E. coli infections in the study area should be based on results of sensitivity tests.

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