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Follow recent developments in antibiotic research
In 10 seconds? Scientists from the Scripps Research Institute recently announced the development of an ultra-strong version of the antibiotic vancomycin, making it up to 1000 more potent against highly dangerous infections.
Why is this so urgent? Dangerous bacteria are constantly evolving resistance strategies against our most valuable medicines, with experts warning that we may soon be facing a post-antibiotic era. Research by the Wellcome Trust indicates that without urgent action, global deaths from antibiotic-resistant infections will overtake those from cancer by 2050, while the CDC currently lists vancomycin-resistant enterococci on its “serious threats” list.
How did they do it? The researchers took the existing vancomycin molecule and made three chemical modifications, two of which prevent bacteria from synthesising their cell wall and one that allows better binding of the drug to its bacterial targets. These modifications confer three additional and independent antimicrobial functions. Because of this, resistance to the drug is likely to emerge slowly, if at all. It was also found to be safe in human and mouse cells even at very high doses.
When will it hit the clinics? The new drug has yet to go through clinical trials, so it will be at least five years before it may be prescribed by doctors.
What else is being done? The urgency of the current situation has caused a revival in antimicrobial research. For example, scientists have recently discovered a previously unknown class of antibiotic in bacteria naturally inhabiting the human nose, while others are trying to engineer viruses to fight of bacterial infections at pig farms.
What about the non-scientists? It's all about reducing the amount of antibiotics that we use to prevent resistance from emerging. For example, doctors are urged to prescribe less of them, while pharmacies are discouraged from selling them over the counter. Farm animals are routinely fed the drugs to promote growth, highlighting another key area for improvement. Finally, streamlining the regulatory process for potential new drugs could incentivise their development by pharmaceutical companies.
Abstract: Subsequent to binding pocket modifications designed to provide dual d-Ala-d-Ala/d-Ala-d-Lac binding that directly overcome the molecular basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide additional synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of d-Ala-d-Ala/d-Ala-d-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin-resistant Enterococci (VRE). Furthermore, it is shown that this type of C-terminal modification may be combined with a second peripheral (4-chlorobiphenyl)methyl (CBP) addition to the vancomycin disaccharide to provide even more potent antimicrobial agents [VRE minimum inhibitory concentration (MIC) = 0.01-0.005 μg/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires d-Ala-d-Ala/d-Ala-d-Lac binding. Finally, it is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Pub.: 01 Jun '17, Pinned: 02 Jun '17
Abstract: A-type resistance towards "last-line" glycopeptide antibiotic vancomycin in the leading hospital acquired infectious agent, the enterococci, is the most common in the UK. Resistance is regulated by the VanRASA two-component system, comprising the histidine sensor kinase VanSA and the partner response regulator VanRA. The nature of the activating ligand for VanSA has not been identified, therefore this work sought to identify and characterise ligand(s) for VanSA. In vitro approaches were used to screen the structural and activity effects of a range of potential ligands with purified VanSA protein. Of the screened ligands (glycopeptide antibiotics vancomycin and teicoplanin, and peptidoglycan components N-acetylmuramic acid, D-Ala-D-Ala and Ala-D-y-Glu-Lys-D-Ala-D-Ala) only glycopeptide antibiotics vancomycin and teicoplanin were found to bind VanSA with different affinities (vancomycin 70 μM; teicoplanin 30 and 170 μM), and were proposed to bind via exposed aromatic residues tryptophan and tyrosine. Furthermore, binding of the antibiotics induced quicker, longer-lived phosphorylation states for VanSA, proposing them as activators of type A vancomycin resistance in the enterococci.
Pub.: 18 May '17, Pinned: 02 Jun '17
Abstract: Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant Enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.
Pub.: 03 Jun '17, Pinned: 04 Jun '17
Abstract: Due to the increasing selection and prevalence of multidrug-resistant gram-negative bacteria and the insufficient development of novel antibiotics, the responsible and prudent use of the available antimicrobial drugs is of major importance. In Germany the rational use of anti-infectives considering the local antimicrobial resistance situation is defined in the infection protection act of 2011. An important tool to follow legal regulations and to improve the treatment of bacterial infections is the antimicrobial stewardship (AMS) concept. Hospitals implementing an AMS program charge a multidisciplinary team of experts to develop and monitor treatment standards and to establish a system of regular consultations and ward rounds. Objectives of this set of measures are the optimization of the individual treatment outcome and on a longer range the improvement of the epidemiological situation. AMS programs include all clinical disciplines that use antimicrobials. Trauma surgery is also affected in a special way as soon as complicated infections and those with multidrug-resistant bacteria are treated.
Pub.: 14 Jun '17, Pinned: 18 Jun '17
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high rates of treatment failure in adults. The epidemiology, clinical outcomes, and risk factors for treatment failure associated with MRSA bacteremia in children are poorly understood.Multicenter, retrospective cohort study of children ≤18 years hospitalized with MRSA bacteremia across 3 tertiary care children's hospitals from 2007 to 2014. Treatment failure was defined as persistent bacteremia >3 days, recurrence of bacteremia within 30 days, or attributable 30-day mortality. Potential risk factors for treatment failure, including the site of infection, vancomycin trough concentration, critical illness, and need for source control, were collected via manual chart review and evaluated using multivariable logistic regression.Of 232 episodes of MRSA bacteremia, 72 (31%) experienced treatment failure and 23% developed complications, whereas 5 (2%) died within 30 days. Multivariable analysis of 174 children treated with vancomycin with steady-state vancomycin concentrations obtained found that catheter-related infections (odds ratio [OR], 0.36; 95% confidence interval [CI]: 0.13-0.94) and endovascular infections (OR, 4.35; 95% CI: 1.07-17.7) were associated with lower and higher odds of treatment failure, respectively, whereas a first vancomycin serum trough concentration <10 μg/mL was not associated with treatment failure (OR, 1.34; 95% CI, 0.49-3.66). Each additional day of bacteremia was associated with a 50% (95% CI: 26%-79%) increased odds of bacteremia-related complications.Hospitalized children with MRSA bacteremia frequently suffered treatment failure and complications, but mortality was low. The odds of bacteremia-related complications increased with each additional day of bacteremia, emphasizing the importance of achieving rapid sterilization.
Pub.: 01 Jun '17, Pinned: 02 Jun '17
Abstract: The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.
Pub.: 27 Jul '16, Pinned: 02 Jun '17
Abstract: Antimicrobial resistance is dominating scientific media. We are warned of an impending 'antibiotic apocalypse', where mankind faces its biggest threat, untreatable microbes. However, the world is not ending. Scientists are responding to the threat; new knowledge and chemotherapeutics are being created to safeguard our future. The future is bright, not gloomy.
Pub.: 28 Dec '16, Pinned: 02 Jun '17
Abstract: Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
Pub.: 07 Jan '15, Pinned: 05 Jun '17
Abstract: Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing medical threat, are almost absent from the future pharmaceutical pipeline.This drug evaluation focuses on the position of doripenem, a novel forthcoming carbapenem. Mechanisms of resistance and new drugs with anti-Gram-negative activity are also briefly reviewed.Literature search was performed for new carbapenems, new antibiotics, doripenem, metallo-beta-lactamase inhibitors, multidrug-resistant pathogens, antipseudomonal antibiotics and multidrug-resistant epidemiology.Doripenem possesses a broad spectrum of activity against Gram-negative bacteria, similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem exhibits rapid bactericidal activity with 2 - 4-fold lower MIC values, compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic applications could offer a treatment opportunity against strains exhibiting borderline resistance to doripenem. Stability against numerous beta-lactamases, low adverse event potential and more potent in vitro antibacterial activity against P. aeruginosa and A. baumanni compared to the existing carbapenems, are its principal features.
Pub.: 02 May '08, Pinned: 02 Jun '17
Abstract: Vancomycin Resistant Enterococci (VRE) are a major cause of nosocomial infections. There are various phenotypic and genotypic methods of detection of glycopeptide resistance in enterococci. This study utilizes multiplex PCR for reliable detection of various glycopeptides resistance genes in VRE.This study was conducted to detect and to assess the prevalence of vancomycin resistance among enterococci isolates. From October 2011 to June 2013, a total of 96 non-repetitive isolates of enterococci from various clinical samples were analyzed. VRE were identified by Kirby Bauer disc diffusion method with Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) of all isolates for vancomycin and teicoplanin was determined by E-test. Multiplex PCR was carried out for all enterococci isolates using six sets of primers.Out of 96 isolates, 14 (14.6%) were found to be resistant to vancomycin by vancomycin E-test method (MIC ≥32 μg/ml). Out of these 14 isolates, 13 were also resistant to teicoplanin (MIC ≥16 μg/ml). VanA gene was detected in all the 14 isolates by Multiplex PCR. One of the PCR amplicons was sent for sequencing and the sequence received was submitted in the GenBank (GenBank accession no. KF181100).Prevalence of VRE in this study was 14.6%. Multiplex PCR is a robust, sensitive and specific technique, which can be used for rapid detection of various glycopeptide resistance genes. Rapid identification of patients infected or colonized with VRE is essential for implementation of appropriate control measures to prevent their spread.
Pub.: 23 Jan '15, Pinned: 02 Jun '17
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